Novel inhibitors of IMPDH enzyme

ABSTRACT

The present invention discloses the identification of the novel inhibitors of IMPDH (inosine-5′-monophosphate dehydrogenase). The compounds and pharmaceutical compositions disclosed herein are useful in treating or preventing IMPDH associated disorders, such as transplant rejection and autoimmune diseases.

[0001] This application claims priority from provisional U.S.Application Serial No. 60/106,180, filed Oct. 29, 1998, which isincorporated herein by reference in its entirety.

FIELD OF THE INVENTION

[0002] The present invention relates to novel compounds which inhibitIMPDH. The invention also encompasses pharmaceutical compositionscomprising these compounds. The compounds and pharmaceuticalcompositions of the invention are particularly well suited forinhibiting IMPDH enzyme activity and, consequently, may beadvantageously used as therapeutic agents for IMPDH-associateddissorders. This invention also relates to methods for inhibiting theactivity of IMPDH using the compounds of this invention and relatedcompounds.

BACKGROUND OF THE INVENTION

[0003] Inosine monophosphate dehydrogenase (IMPDH) has been shown to bea key enzyme in the regulation of cell proliferation anddifferentiation. Nucleotides are required for cells to divide andreplicate. In mammals, nucleotides may be synthesized through one of twopathways: the de novo synthesis pathway or the salvage pathway. Theextent of utilization of each pathway is dependent on the cell type.This selectivity has ramifications with regard to therapeutic utility asdescribed below.

[0004] IMPDH is involved in the de novo synthesis of guanosinenucleotides. IMPDH catalyzes the irreversible NAD-dependent oxidation ofinosine-5′-monophosphate (“IMP”) to xanthosine-5′-monophosphate (“XMP”),Jackson et al., Nature 256:331-333 (1975).

[0005] IMPDH is ubiquitous in eukaryotes, bacteria and protozoa. Theprokaryotic forms share 30-40% sequence identity with the human enzyme.

[0006] Two distinct cDNA's encoding IMPDH have been identified andisolated. These transcripts are labeled type I and type II and are ofidentical size (514 amino acids). Collart et al., J. Biol. Chem.263:15769-15772 (1988); Natsumeda et al., J. Biol. Chem. 265:5292-5295(1990); and U.S. Pat. No. 5,665,583 to Collart et al. These isoformsshare 84% sequence identity. IMPDH type I and type II form tetramers insolution, the enzymatically active unit.

[0007] B and T-lymphocytes depend on the de novo, rather than salvagepathway, to generate sufficient levels of nucleotides necessary toinitiate a proliferative response to mitogen or antigen. Due to the Band T cell's unique reliance on the de novo pathway, IMPDH is anattractive target for selectively inhibiting the immune system withoutalso inhibiting the proliferation of other cells.

[0008] Immunosuppression has been achieved by inhibiting a variety ofenzymes. Examples include: phosphatase calcineurin (inhibited bycyclosporin and FK-506); dihydroorotate dehydrogenase (DHODase), anenzyme involved in the biosynthesis of pyrimidines (inhibited byleflunomide and brequinar); the kinase FRAP (inhibited by rapamycin);and the heat shock protein hsp70 (inhibited by deoxyspergualin).

[0009] Inhibitors of IMPDH have also been described in the art. WO97/40028 and U.S. Pat. No. 5,807,876 describe a class of ureaderivatives that possess a common urea backbone. A large number ofcompounds are described in WO 97/40028 and U.S. Pat. No. 5,807,876, butseveral of the compounds suffer from drawbacks such as inferiorsolubility. A recent publication, WO 98/40381, describes a series ofheterocyclic substituted anilines as inhibitors of IMPDH.

[0010] U.S. Pat. Nos. 5,380,879 and 5,444,072 and PCT publications WO94/01105 and WO 94/12184 describe mycophenolic acid (“MPA”) and some ofits derivatives as potent, uncompetitive, reversible inhibitors of humanIMPDH type I and type II. MPA has been demonstrated to block theresponse of B and T-cells to mitogen or antigen. Immunosuppressants,such as MPA and derivatives of MPA, are useful drugs in the treatment oftransplant rejection and autoimmune disorders, psoriasis, inflammatorydiseases, including, rheumatoid arthritis, tumors and for the treatmentof allograft rejection. These are described in U.S. Pat. Nos. 4,686,234,4,725,622, 4,727,069, 4,753,935, 4,786,637, 4,808,592, 4,861,776,4,868,153, 4,948,793, 4,952,579, 4,959,387, 4,992,467; 5.247,083; andU.S. patent application Ser. No. 07/927,260, filed Aug. 7, 1992. MPAdoes display undesirable pharmacological properties, such asgastrointestinal toxicity and poor bioavailability.

[0011] Tiazofurin, ribavirin and mizoribine also inhibit IMPDH. Thesenucleoside analogs are competitive inhibitors of TMPDH, however theseagents inhibit other NAD dependent enzymes. This low level ofselectivity for IMPDH limits the therapeutic application of tiazofurin,ribavirin and mizoribine. Thus, new agents which have improvedselectivity for IMPDH would represent a significant improvement over thenucleoside analogs.

[0012] Mycophenolate mofetil, sold under the trade name CELLCEPT, is aprodrug which liberates MPA in vivo. It is approved for use inpreventing acute renal allograft rejection following kidneytransplantation. The side effect profile limits the therapeuticpotential of this drug. MPA is rapidly metabolized to the inactiveglucuronide in vivo. In humans, the blood levels of glucuronide exceedthat of MPA. The glucuronide undergoes enterohepatic recycling causingaccumulation of MPA in the bile and subsequently in the gastrointestinaltract. This together with the production of the inactive glucuronideeffectively lowers the drug's in vivo potency, while increasing itsundesirable gastrointestinal side effects.

[0013] Unlike type I, type II mRNA is preferentially upregulated inhuman leukemic cell lines K562 and HL-60. Weber, J. Biol. Chem. 266:506-509 (1991). In addition, cells from human ovarian tumors andleukemic cells from patients with chronic granulocytic, lymphocytic andacute myeloid leukemias also display an up regulation type II mRNA. Thisdisproportionate increase in IMPDH activity in malignant cells may beaddressed through the use of an appropriate IMPDH inhibitor. IMPDH hasalso been shown to play a role in the proliferation of smooth musclecells, indicating that inhibitors of IMPDH may be useful in preventingrestenosis or other hyperproliferative vascular diseases.

[0014] IMPDH has been shown to play a role in viral replication in someviral cell lines. Carr, J. Biol. Chem. 268:27286-27290 (1993). The IMPDHinhibitor VX-497, is currently being evaluated for the treatment ofhepatitis C virus in humans. Ribavirin has also been used in thetreatment of hepatitis C and B viruses and when used in combination withinterferon an enhancement in activity was observed. The IMPDH inhibitorribavirin is limited by its lack of a sustained response in monotherapyand broad cellular toxicity.

[0015] There remains a need for potent selective inhibitors of IMPDHwith improved pharmacological properties, physical properties and fewerside effects. Such inhibitors would have therapeutic potential asimmunosuppressants, anti-cancer agents, anti-vascular hyperproliferativeagents, antiinflammatory agents, antifungal agents, antipsoriatic andanti-viral agents. The compounds of the present invention differ fromthose taught by the prior art and are effective inhibitors of IMPDH.

SUMMARY OF THE INVENTION

[0016] The present invention provides compounds of the following formulaI, stereoisomeric forms thereof, tautomeric forms thereof,pharmaceutically acceptable salt forms thereof, or prodrug formsthereof, for use as inhibitors of IMPDH enzyme:

[0017] wherein:

[0018] Z is a monocyclic or bicyclic ring system optionally containingup to 4 heteroatoms selected from N, O, and S, and wherein a CH₂adjacent to any of the said N, O or S heteroatoms is optionallysubstituted with oxo (═O), and wherein Z is optionally substituted with0-5 substituents chosen from R¹, R², R³ or R⁴;

[0019] R¹ and R² are each independently selected from the groupconsisting of H, F, Cl, Br, I, NO₂, CF₃, CN, OCF₃, OH, C₁-C₄alkoxy-,C₁-C₄alkylcarbonyl-, C₁-C₆ alkyl, hydroxy C₁-C₄ alkyl-, C₃-C₆ alkenyl,C₃-C₆ alkynyl, C₃-C₁₀ cycloalkyl(C₀-C₄alkyl)-, H₂N(C₀-C₄)alkyl-,R⁶HN(C₀-C₄)alkyl-, R⁶R⁷N(C₀-C₄)alkyl-, R⁷S(C₀-C₄)alkyl-,R⁷S(O)(C₀-C₄)alkyl-, R⁷SO₂(C₀-C₄)alkyl-, R⁶NSO₂(C₀-C₄)alkyl-, HSO₃,HO₂C(C₀-C₄)alkyl-, R⁶O₂C(C₀-C₄)alkyl-, and R⁶R⁷NCO(C₀-C₄)alkyl-, or

[0020]  alternatively, R¹ and R², when on adjacent carbon atoms, may betaken together to be methylenedioxy or ethylenedioxy;

[0021] R³ is a 5- or 6-membered heterocyclic ring system containing upto 4 heteroatoms selected from N, O, and S, said heterocyclic ringsystem being optionally substituted with 0-3 R⁵, wherein when R⁵ ishydroxy the heterocycle may undergo tautomerization to an oxo species ormay exist as an equilibrium mixture of both tautomers;

[0022] R⁴ is selected from F, Cl, Br, I, NO₂, CF₃, CN, C₁-C₄alkoxy-, OH,oxo, CF₃O, haloalkyloxy, C₀-C₄ alkylhydroxy, C₁-C₄ alkyl-, C₁-C₄alkylcarbonyl-, C₀-C₄ alkylOCOR⁶, C₀-C₄ alkylOC(═O)OR⁶, C₀-C₄alkylOC(═O)NR⁶R⁷, NH₂, NHR⁶, C₀-C₄ alkylNR⁶R⁷, C₀-C₄ alkylNR⁷C(═O)OR⁶,C₀-C₄ alkylNR⁶SO₂NR⁶R⁷, C₀-C₄ alkylNR⁷SO₂R⁶, C₀-C₄ alkylSR⁶, C₀-C₄alkylS(O)R⁶, C₀-C₄ alkylSO₂R⁶, SO₃R⁷, C₀-C₄ alkylSO₂NR⁶R⁷, C₀-C₄alkylSO₂NR⁷CO(CR⁹R¹⁰)₀₋₃R⁶, C₀-C₄ alkylCO₂H, C₀-C₄ alkylCO₂R⁶, C₀-C₄alkylCONR⁶R⁷, and C₀-C₄alkylCONR⁷SO₂(CR⁹R¹⁰)₀₋₃R⁶;

[0023] R⁵ is selected from the group consisting of H, C₁-C₄ alkyl, C₃-C₇cycloalkyl, F, Cl, Br, I, NO₂, CN, CF₃, OCF₃, OH, oxo, C₁-C₄alkoxy-,hydroxyC₁-C₄ alkyl-, C₁-C₄ alkylcarbonyl-, CO₂H, CO₂R⁶, CONR⁶R⁷, NHR⁶,and NR⁶R⁷;

[0024] R⁶ is selected from the group consisting of H, C₁-C₈ alkyl, C₃-C₆alkenyl, C₃-C₆ alkynyl, C₃-C₁₀ cycloalkyl(C₀-C₄ alkyl)-, aryl(C₀-C₄alkyl)-, and heterocyclic (C₀C₄ alkyl)-,

[0025]  wherein said aryl or heterocyclic groups are substituted with0-2 substituents independently selected from the group consisting ofC₁-C₄ alkyl, C₁-C₄ alkoxy, hydroxy C₀-C₄ alkyl, oxo, F, Cl, Br, CF₃,NO₂, CN, OCF₃, NH₂, NHR⁷, NR⁷R⁸, SR⁷, S(O)R⁷, SO₂R⁷, SO₂NR⁷R⁸, CO₂H,CO₂R⁷, and CONR⁷R⁸;

[0026] R⁷ and R⁸ are each independently selected from the groupconsisting of H, C₁-C₈ alkyl, C₃-C₆ alkenyl, C₃-C₆ alkynyl, C₃-C₁₀cycloalkyl(C₀-C₄ alkyl)-, C₁- C₆ alkylcarbonyl, C₃-C₇ cycloalkyl(C₀-C₅alkyl)carbonyl, C₁-C₆ alkoxycarbonyl, C₃-C₇ cycloalkyl(C₀-C₅alkoxy)carbonyl, aryl(C₁-C₅ alkoxy)carbonyl, arylsulfonyl, aryl(C₀C₄alkyl)-, heterocyclic(C₁-C₅ alkoxy)carbonyl, heterocyclic sulfonyl andheterocyclic (C₀-C₄ alkyl)-, wherein said aryl or heterocyclic groupsare substituted with 0-2 substituents independently selected from thegroup consisting of C₁-C₄ alkyl, C₁-C₄ alkoxy, F, Cl, Br, CF₃, CN, andNO₂;

[0027] alternatively, R⁶ and R⁷, or R⁶ and R⁸, or R⁷ and R⁸, when bothsubstituents are on the same nitrogen atom [as in (—NR⁶R⁷) or (—NR⁷R⁸)],can be taken together with the nitrogen atom to which they are attachedto form a heterocycle selected from the group consisting of1-aziridinyl, 1-azetidinyl, 1-piperidinyl, 1-morpholinyl,1-pyrrolidinyl, thiamorpholinyl, thiazolidinyl, and 1-piperazinyl, saidheterocycle being optionally substituted with 0-3 groups selected fromthe group consisting of oxo, C₁-C₆ alkyl, C₃-C₇ cycloalkyl(C₀-C₄alkyl)-, C₁-C₆ alkylcarbonyl, C₃-C₇ cycloalkyl(C₀-C₅ alkyl)carbonyl,C₁-C₆ alkoxycarbonyl, C₃-C₇ cycloalkyl(C₀-C₅ alkoxy)carbonyl, aryl(C₀-C₅alkyl), heterocyclic(C₀-C₅ alkyl), aryl(C₁-C₅ alkoxy)carbonyl,heterocyclic(C₁-C₅ alkoxy)carbonyl, C₁-C₆ alkylsulfonyl, arylsulfonyl,and heterocyclicsulfonyl,

[0028]  wherein said aryl or heterocyclic groups are substituted with0-2 substituents independently selected from the group consisting ofC₁-C₄ alkyl, C₁-C₄ alkoxy, F, Cl, Br, CF₃, CN, and NO₂;

[0029] J is selected from the group consisting of —NR⁷— and —C(═O)—;

[0030] K is selected from the group consisting of —NR⁷—, —C(═O)—, and—CHR⁹—;

[0031] L is selected from the group consisting of a single bond, —C(═O),—CR¹⁰R¹¹—, —C(═O)CR¹⁰R¹¹—, —CR¹⁰R¹¹C(═O)—, —CR¹⁰OR¹¹C(═O)—,—HR¹⁵C—CHR¹⁶—, and R¹⁵C═CR¹⁶;

[0032] R⁹ is selected from the group consisting of H, C₁-C₈ alkyl, C₃-C₆alkenyl, C₃-C₁₀ cycloalkyl(C₀-C₄ alkyl)-, aryl(C₀-C₄ alkyl)-, andheterocyclic(C₀-C₄ alkyl)-,

[0033]  wherein said aryl or heterocyclic groups are substituted with0-2 substituents independently selected from the group consisting ofC₁-C₄ alkyl, C₁-C₄ alkoxy, F, Cl, Br, CF₃, and NO₂;

[0034] R¹⁰ is selected from the group consisting of H, F, Cl, Br, C₁-C₆alkoxy, C₁-C₈ alkyl, C₃-C₆ alkenyl, C₃-C₁₀ cycloalkyl(C₀-C₄ alkyl)-,aryl(C₀-C₄ alkyl)-, and heterocyclic(C₀-C₄ alkyl)-, wherein said aryl orheterocyclic groups are substituted with 0-2 substituents independentlyselected from the group consisting of C₁-C₄ alkyl, C₁-C₄ alkoxy, F, Cl,Br, CF₃, CN, and NO₂;

[0035] R¹¹ is selected from the group consisting of H, F, Cl, Br, OMe,C₁-C₈ alkyl, C₃-C₆ alkenyl, C₃-C₁₀ cycloalkyl(C₀-C₄ alkyl)-, aryl(C₀-C₄alkyl)-, and heterocyclic(C₀-C₄ alkyl)-, wherein said aryl orheterocyclic groups are substituted with 0-2 substituents independentlyselected from the group consisting of C₁-C₄ alkyl, C₁-C₄ alkoxy, F, Cl,Br, CF₃, CN, and NO₂;

[0036] alternatively, R¹⁰ and R¹¹, when on the same carbon atom [as in(—CR¹⁰R¹¹—)], can be taken together with the carbon atoms to which theyare attached to form a 3-7 membered carbocyclic or 3-7 memberedheterocyclic non-aromatic ring system, said carbocyclic or heterocyclicring being optionally substituted with 0-2 substituents independentlyselected from the group consisting of C₁-C₄ alkyl, C₁-C₄ alkoxy, hydroxyC₀-C₄ alkyl, oxo, F, Cl, Br, CF₃, and NO₂;

[0037] X is selected from the group consisting of OR¹², NR¹²R¹³, C₁-C₈alkyl, C₃-C₆ alkenyl, C₃-C₁₀ cycloalkyl(C₀-C₄ alkyl)-, C₆-C₁₀ aryl(C₀-C₄alkyl)-, and heterocyclic(C₀-C₄ alkyl)-,

[0038]  wherein said aryl or heterocyclic groups are substituted with0-3 substituents independently selected from R¹⁴, with the proviso thatwhen L is a single bond, X cannot be NR¹²R¹³;

[0039] R¹² is selected from the group consisting of H, C₁-C₈ alkyl,C₃-C₆ alkenyl, C₃-C₁₀ cycloalkyl(C₀-C₄ alkyl)-, monocyclic or bicyclicaryl(C₀-C₄ alkyl)-, and monocyclic or bicyclic 5-10 memberedheterocyclic(C₀-C₄ alkyl)-, and —CZ¹Z²Z³,

[0040]  wherein said aryl or heterocyclic groups are substituted with0-3 substituents independently selected from R¹⁴;

[0041] Z¹ is selected from the group consisting of C₁-C₈ alkyl, C₂-C₆alkenyl, C₂-C₆ alkynyl, C₁-C₆ hydroxyalkyl, C₁-C₄ alkoxy C₁-C₄ alkyl,aryl(C₀-C₄ alkyl)-, and 4-10 membered heterocyclic (C₀-C₄ alkyl)-,

[0042]  wherein said aryl or heterocyclic groups are substituted with0-3 substituents independently selected from R¹⁴;

[0043] Z² is selected from the group consisting of C₁-C₈ alkyl, C₂-C₆alkenyl, C₂-C₆ alkynyl, C₁-C₆ hydroxyalkyl, C₁-C₄ alkoxy C₁-C₄ alkyl,C₁-C₆ NR¹⁷R¹⁸, aryl(C₀-C₄ alkyl)-, and 4-10 membered heterocyclic (C₀-C₄alkyl)-,

[0044]  wherein said aryl or heterocyclic groups are substituted with0-3 substituents independently selected from R¹⁴;

[0045] Z³ is selected from the group consisting of C₁-C₈ alkyl,R¹⁴(C₂-C₄ alkyl)-, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₁-C₆ hydroxyalkyl,C₁-C₄ alkoxy C₁-C₄ alkyl, aryl(C₀-C₄ alkyl)-, 4-10 membered heterocyclic(C₀-C₄ alkyl)-, R¹⁷O═C(C₀-C₄ alkyl)-, R¹⁷OO═C(C₀-C₄ alkyl)-, andR¹⁷R¹⁸NO═C(C₀-C₄ alkyl)-,

[0046]  wherein said aryl or heterocyclic groups are substituted with0-3 substituents independently selected from R¹⁴;

[0047] alternatively, Z¹ and Z², when on the same carbon atom [as in(—CZ¹Z²—)], can be taken together with the carbon atoms to which theyare attached to form a 3-7 membered carbocyclic or 3-7 memberedheterocyclic non-aromatic ring system, said carbocyclic or heterocyclicring being optionally substituted with 0-2 substituents independentlyselected from R¹⁴.

[0048] R¹³ is selected from the group consisting of H, C₁-C₈ alkyl,C₃-C₆ alkenyl, C₃-C₁₀ cycloalkyl(C₀-C₄ alkyl)-, C₁-C₆ alkylcarbonyl,C₁-C₆ alkylsulfonyl, C₃-C₇ cycloalkyl(C₀-C₅ alkyl)carbonyl, C₁-C₆alkoxycarbonyl, C₃-C₇ cycloalkyl(C₀-C₅ alkoxy)carbonyl, aryl(C₀-C₄alkyl)-, aryl(C₁-C₅ alkoxy)carbonyl , arylsulfonyl, heterocyclic(C₀-C₄alkyl), heterocyclic(C₁-C₅ alkoxy)carbonyl, and heterocyclicsulfonyl,

[0049]  wherein said aryl or heterocyclic groups are substituted with0-2 substituents independently selected from the group consisting ofC₁-C₄ alkyl, C₁-C₄ alkoxy, F, Cl, Br, CF₃, CN, and NO₂;

[0050] alternatively, R¹² and R¹³, when both are on the same nitrogenatom [as in (—NR¹²R¹³)] can be taken together with the nitrogen atom towhich they are attached to form a heterocycle selected from1-aziridinyl, 1-azetidinyl, 1-piperidinyl, 1-morpholinyl,1-pyrrolidinyl, thiamorpholinyl, thiazolidinyl, and 1-piperazinyl,

[0051]  said heterocycle being optionally substituted with 0-3 groupsindependently selected from oxo, C₁-C₆ alkyl, C₃-C₇ cycloalkyl(C₀-C₄alkyl)-, C₁-C₆ alkylcarbonyl, C₃-C₇ cycloalkyl(C₀-C₅ alkyl)carbonyl,C₁-C₆ alkoxycarbonyl, C₃-C₇ cycloalkyl(C₀-C₅ alkoxy)carbonyl, aryl(C₀-C₅alkyl), heterocyclic(C₀-C₅ alkyl), aryl(C₁-C₅ alkoxy)carbonyl,heterocyclic(C₁-C₅ alkoxy)carbonyl, C₁-C₆ alkylsulfonyl arylsulfonyl andheterocyclicsulfonyl,

[0052]  wherein said aryl or heterocyclic groups are substituted with0-2 substituents independently selected from the group consisting ofCH₃—, alkoxy, F, Cl, Br, CF₃, CN, and NO₂;

[0053] R¹⁴ is selected from the group consisting of H, C₁-C₁₀ alkyl,NO₂, CF₃, CN, F, Cl, Br, C₁-C₁₀ alkylcarbonyl, haloalkyl, haloalkoxy,OH, NR⁶R⁷(C₀-C₄ alkyl)-, R⁶C(═O)O(C₀-C₄ alkyl)-, R⁶OC(═O)O(C₀-C₄alkyl)-, R⁶O(C₀-C₄ alkyl), R⁶R⁷NC(═O)O(C₀-C₄ alkyl)-, R⁶R⁷NC(═O)(C₀-C₄alkyl)-, R⁶O(CR¹⁰R¹¹)₂₋₆R⁶NC(═O)(C₀-C₄ alkyl)-,R⁶R⁷N(CR¹⁰R¹¹)₂₋₆R⁶NC(═O)(C₀-C₄ alkyl)-, R⁶O₂C(CH₂)₁₋₄O(C₀-C₄ alkyl)-,R⁶OOC(C₁-C₄ alkoxy)-, R⁶OOC(C₀-C₄ alkyl)-, R⁶C(═O)(C₀-C₄ alkyl)-,R⁶C(═O)NR⁷(C₀-C₄ alkyl)-, R⁶OC(═O)NR⁷(C₀-C₄ alkyl)-, R⁶OC(═NCN)NR⁷(C₀-C₄alkyl)-, R⁶R⁷NC(═O)NR⁸(C₀-C₄ alkyl)-, R⁶OC(═NC)NR⁷(C₀-C₄ alkyl)-,R⁶(CR¹⁰R¹¹)₁₋₄ NR⁷C═O—, R⁶O(CR¹⁰R¹¹)₁₋₄O═CR⁷N—, NR⁶R⁷(CR¹⁰R¹¹)₁₋₄C═OR⁷N—, R⁶O(CR¹⁰R¹¹)₂₋₄R⁷N—, R⁶O₂C(CR¹⁰R¹¹)₁₋₄R⁷N,R⁶R⁷N(CR¹⁰R¹¹)₂₋₄R⁷—, R⁶R⁷NC(═NCN)NR⁷(C₀-C₄ alkyl)-,R⁶R⁷NC(═C(H)(NO₂))NR⁷(C₀-C₄ alkyl)-, R⁷R⁸NC(═NR⁷)NR⁷(C₀-C₄ alkyl)-,R⁶R⁷N SO₂NR⁸(C₀-C₄ alkyl)-, R⁶SO₂NR⁷(C₀-C₄ alkyl)-, R⁶R⁷N(C₁-C₄)CO—,R⁶R⁷N(C₂-C₆ alkyl)O—, R⁶CO(CR¹⁰R¹¹)₀₋₂ R⁷N(O₂)S(C₀-C₄ alkyl),R⁶(O₂)SR⁷NC(═O)(C₀-C₄ alkyl)-, R⁶S(C₀-C₄ alkyl)-, R⁶S(═O)(C₀-C₄ alkyl)-,R⁶SO₂(C₀-C₄ alkyl)-, SO₂NR⁶R⁷, SiMe₃, R⁶R⁷N(C₂-C₄ alkyl)-, R⁶R⁷N(C₂-C₄alkoxy)-, HSO₃, HONH—, R⁶ONH—, R⁸R⁷NNR⁶—, HO(COR⁶)N—, HO(R⁶O₂C)N, C₂-C₆alkenyl, C₃-C₁₀ cycloalkyl, C₃-C₁₀ cycloalkylmethyl, aryl(C₀-C₄alkyl)-,heteroaryl(C₀-C₄alkyl)-, aryl(C₀-C₄alkyl)O—, andheteroaryl(C₀-C₄alkyl)O—.

[0054]  wherein said aryl groups are substituted with 0-2 substituentsindependently selected from a group consisting of C₁-C₄ alkyl, C₁-C₄alkoxy, F, Cl, Br, CF₃, and NO₂;

[0055] R¹⁵ is selected from the group consisting of H, halo, cyano,C₁-C₈ alkyl, C₃-C₆ alkenyl, and C₃-C₁₀ cycloalkyl(C₀-C₄ alkyl)-,aryl(C₀-C₄ alkyl)-, and heterocyclic(C₀-C₄ alkyl)-,

[0056]  wherein said aryl or heterocyclic groups are substituted with0-2 substituents independently selected from R¹⁴;

[0057] R¹⁶ is selected from the group consisting of H, halo, cyano,C₁-C₈ alkyl, C₃-C₆ alkenyl, C₃-C₁₀ cycloalkyl(C₀-C₄ alkyl)-, aryl(C₀-C₄alkyl)-, and heterocyclic(C₀-C₄ alkyl)-,

[0058]10 wherein said aryl or heterocyclic groups are substituted with0-2 substituents independently selected from R¹⁴;

[0059] alternatively, when R¹⁵ and R¹⁶ are on adjacent carbon atoms [asin —HR¹⁵C—CHR¹⁶—], or when R¹⁵ and R¹⁶ are oriented on the same side ofthe double bond [as in the following structure (III)

[0060]  R¹⁵ and R¹⁶ can be taken together with the carbon atoms to whichthey are attached to form a 3-7 membered carbocyclic aromatic ornonaromatic ring system, or a 3-7 membered heterocyclic aromatic ornonaromatic ring system, said carbocyclic or heterocyclic ring beingoptionally substituted with 0-2 substituents independently selected fromthe group consisting of C₁-C₄ alkyl, C₁-C₄ alkoxy, F, Cl, Br, CF₃, NO₂;

[0061] R¹⁷ is selected from the group consisting of H, C₁-C₈ alkyl,C₃-C₆ alkenyl, C₃-C₁₀ cycloalkyl(C₀-C₄ alkyl)-, C₁-C₆ alkylcarbonyl,C₁-C₆ alkylsulfonyl, C₃-C₇ cycloalkyl(C₀-C₅ alkyl)carbonyl, C₁-C₆alkoxycarbonyl, C₃-C₇ cycloalkyl(C₀-C₅ alkoxy)carbonyl,hydroxy(C₂-C₄)alkyl-, C₁-C₃ alkoxy(C₂-C₄)alkyl-, (C₀-C₄ alkyl)(C₀-C₄alkyl) amino(C₂-C₄)alkyl-, aryl(C₀-C₄ alkyl)-, aryl(C₁-C₅alkoxy)carbonyl, arylsulfonyl, heterocyclic(C₀-C₄ alkyl),heterocyclic(C₁-C₅ alkoxy)carbonyl, and heterocyclicsulfonyl,

[0062]  wherein said aryl or heterocyclic groups are substituted with0-2 substituents independently selected from the group consisting ofC₁-C₄ alkyl, C₁-C₄ alkoxy, C₁-C₄ alkoxy C₁-C₄ alkyl, oxo, F, Cl, Br,CF₃, CN, and NO₂;

[0063] R¹⁸ is selected from the group consisting of H, C₁-C₈ alkyl,C₃-C₆ alkenyl, C₃-C₁₀ cycloalkyl(C₀-C₄ alkyl)-, aryl(C₀-C₄ alkyl)-, andheterocyclic(C₀-C₄ alkyl),

[0064]  wherein said aryl or heterocyclic groups are substituted with0-2 substituents independently selected from the group consisting ofC₁-C₄ alkyl, C₁-C₄ alkoxy, F, Cl, Br, CF₃, CN, and NO₂; and

[0065] alternatively, R¹⁷ and R¹⁸, when both are on the same nitrogenatom [as in (—NR¹²R¹³)] can be taken together with the nitrogen atom towhich they are attached to form a heterocycle selected from1-aziridinyl, 1-azetidinyl, 1-piperidinyl, 1-morpholinyl,1-pyrrolidinyl, thiamorpholinyl, thiazolidinyl, and 1-piperazinyl,

[0066]  said heterocycle being optionally substituted with 0-3 groupsselected from oxo, C₁-C₆ alkyl, C₃-C₇ cycloalkyl(C₀-C₄ alkyl)-, C₁-C₆alkylcarbonyl, (C₁-C₆ alkylcarbonyl)(C₀-C₄alkyl)amino-, C₃-C₇cycloalkyl(C₀-C₅ alkyl)carbonyl, C₁-C₆ alkoxycarbonyl, C₃-C₇cycloalkyl(C₀-C₅ alkoxy)carbonyl, aryl(C₀-C₅ alkyl), heterocyclic(C₀-C₅alkyl), aryl(C₁-C₅ alkoxy)carbonyl, heterocyclic(C₁-C₅ alkoxy)carbonyl,C₁-C₆ alkylsulfonyl arylsulfonyl and heterocyclicsulfonyl,

[0067]  wherein said aryl or heterocyclic groups are substituted with0-2 substituents independently selected from the group consisting ofCH₃—, alkoxy, F, Cl, Br, CF₃, CN, and NO₂.

[0068] Compounds of formula I, their enantiomers, diasteromers,tautomers and pharmaceutically acceptable salts, prodrugs and solvatesthereof, are novel.

[0069] The present invention also provides pharmaceutical compositionscomprising the compounds of formula I and methods of treatingIMPDH-associated disorders using the compounds of formula I.

[0070] The compounds of the present invention offer therapeuticadvantages over known prior art compounds, and are useful in treatingIMPDH-associated disorders. These advantages include increasedsolubility (which in turn increases overall therapeutic benefit) andreduction in negative side effects.

DETAILED DESCRIPTION OF THE INVENTION

[0071] As described above, the present invention encompasses compoundsof the following formula I, stereoisomeric forms thereof, tautomericforms thereof, pharmaceutically acceptable salt forms thereof, orprodrug forms thereof:

[0072] wherein:

[0073] Z is a monocyclic or bicyclic ring system optionally containingup to 4 heteroatoms selected from N, O, and S, and wherein a CH₂adjacent to any of the said N, O or S heteroatoms is optionallysubstituted with oxo (═O), and wherein Z is optionally substituted with0-5 substituents chosen from R¹, R², R³ or R⁴;

[0074] R¹ and R² are each independently selected from the groupconsisting of H, F, Cl, Br, I, NO₂, CF₃, CN, OCF₃, OH, C₁-C₄alkoxy-,C₁-C₄alkylcarbonyl-, C₁-C₆ alkyl, hydroxy C₁-C₄ alkyl-, C₃-C₆ alkenyl,C₃-C₆ alkynyl, C₃-C₁₀ cycloalkyl(C₀-C₄alkyl)-, H₂N(C₀-C₄)alkyl-,R⁶HN(C₀-C₄)alkyl-, R⁶R⁷N(C₀-C₄)alkyl-, R⁷S(C₀-C₄)alkyl-,R⁷S(O)(C₀-C₄)alkyl-, R⁷SO₂(C₀-C₄)alkyl-, R⁶NSO₂(C₀-C₄)alkyl-, HSO₃,HO₂C(C₀-C₄)alkyl-, R⁶O₂C(C₀-C₄)alkyl-, and R⁶R⁷NCO(C₀-C₄)alkyl-, or

[0075]  alternatively, R¹ and R², when on adjacent carbon atoms, may betaken together to be methylenedioxy or ethylenedioxy;

[0076] R³ is a 5- or 6-membered heterocyclic ring system containing upto 4 heteroatoms selected from N, O, and S, said heterocyclic ringsystem being optionally substituted with 0-3 R⁵, wherein when R⁵ ishydroxy the heterocycle may undergo tautomerization to an oxo species ormay exist as an equilibrium mixture of both tautomers;

[0077] R⁴ is selected from F, Cl, Br, I, NO₂, CF₃, CN, C₁-C₄alkoxy-, OH,oxo, CF₃O, haloalkyloxy, C₀-C₄ alkylhydroxy, C₁-C₄ alkyl-, C₁-C₄alkylcarbonyl-, C₀-C₄ alkylOCOR⁶, C₀-C₄ alkylOC(═O)OR⁶,C₀-C₄alkylOC(═O)NR⁶R⁷, NH₂, NHR⁶, C₀-C₄ alkylNR⁶R⁷, C₀-C₄alkylNR⁷C(═O)OR⁶, C₀-C₄ alkylNR⁶SO₂NR⁶R⁷, C₀-C₄ alkylNR⁷SO₂R⁶, C₀-C₄alkylSR⁶, C₀-C₄ alkylS(O)R⁶, C₀-C₄ alkylSO₂R⁶, SO₃R⁷, C₀-C₄alkylSO₂NR⁶R⁷, C₀-C₄alkylSO₂NR⁷CO(CR⁹R¹⁰)₀₋₃R⁶, C₀-C₄ alkylCO₂H, C₀-C₄alkylCO₂R⁶, C₀-C₄ alkylCONR⁶R⁷, and C₀-C₄alkylCONR⁷SO₂(CR⁹R¹⁰)₀₋₃R⁶;

[0078] R⁵ is selected from the group consisting of H, C₁-C₄ alkyl, C₃-C₇cycloalkyl, F, Cl, Br, I, NO₂, CN, CF₃, OCF₃, OH, oxo, C₁-C₄alkoxy-,hydroxyC₁-C₄ alkyl-, C₁-C₄ alkylcarbonyl-, CO₂H, CO₂R⁶, CONR⁶R⁷, NHR⁶,and NR⁶R⁷;

[0079] R⁶ is selected from the group consisting of H, C₁-C₈ alkyl, C₃-C₆alkenyl, C₃-C₆ alkynyl, C₃-C₁₀ cycloalkyl(C₀-C₄ alkyl)-, aryl(C₀-C₄alkyl)-, and heterocyclic (C₀-C₄ alkyl)-,

[0080]  wherein said aryl or heterocyclic groups are substituted with0-2 substituents independently selected from the group consisting ofC₁-C₄ alkyl, C₁-C₄ alkoxy, hydroxy C₀-C₄ alkyl, oxo, F, Cl, Br, CF₃,NO₂, CN, OCF₃, NH₂, NHR⁷, NR⁷R⁸, SR⁷, S(O)R⁷, SO₂R⁷, SO₂NR⁷R⁸, CO₂H,CO₂R⁷, and CONR⁷R⁸;

[0081] R⁷ and R⁸ are each independently selected from the groupconsisting of H, C₁-C₈ alkyl, C₃-C₆ alkenyl, C₃-C₆ alkynyl, C₃-C₁₀cycloalkyl(C₀-C₄ alkyl)-, C₁-C₆ alkylcarbonyl, C₃-C₇ cycloalkyl(C₀-C₅alkyl)carbonyl, C₁-C₆ alkoxycarbonyl, C₃-C₇ cycloalkyl(C₀-C₅alkoxy)carbonyl, aryl(C₁-C₅ alkoxy)carbonyl, arylsulfonyl, aryl(C₀-C₄alkyl)-, heterocyclic(C₁-C₅ alkoxy)carbonyl, heterocyclic sulfonyl andheterocyclic (C₀-C₄ alkyl)-, wherein said aryl or heterocyclic groupsare substituted with 0-2 substituents independently selected from thegroup consisting of C₁-C₄ alkyl, C₁-C₄ alkoxy, F, Cl, Br, CF₃, CN, andNO₂;

[0082] alternatively, R⁶ and R⁷, or R⁶ and R⁸, or R⁷ and R⁸, when bothsubstituents are on the same nitrogen atom [as in (—NR⁶R⁷) or (—NR⁷R⁸)],can be taken together with the nitrogen atom to which they are attachedto form a heterocycle selected from the group consisting of1-aziridinyl, 1-azetidinyl, 1-piperidinyl, 1-morpholinyl,1-pyrrolidinyl, thiamorpholinyl, thiazolidinyl, and 1-piperazinyl, saidheterocycle being optionally substituted with 0-3 groups selected fromthe group consisting of oxo, C₁-C₆alkyl, C₃-C₇ cycloalkyl(C₀-C₄ alkyl)-,C₁-C₆ alkylcarbonyl, C₃-C₇ cycloalkyl(C₀-C₅ alkyl)carbonyl, C₁-C₆alkoxycarbonyl, C₃-C₇ cycloalkyl(C₀-C₅ alkoxy)carbonyl, aryl(C₀-C₅alkyl), heterocyclic(C₀-C₅ alkyl), aryl(C₁-C₅ alkoxy)carbonyl,heterocyclic(C₁-C₅ alkoxy)carbonyl, C₁-C₆ alkylsulfonyl, arylsulfonyl,and heterocyclicsulfonyl,

[0083]  wherein said aryl or heterocyclic groups are substituted with0-2 substituents independently selected from the group consisting ofC₁-C₄ alkyl, C₁-C₄ alkoxy, F, Cl, Br, CF₃, CN, and NO₂;

[0084] J is selected from the group consisting of —NR⁷— and —C(═O)—;

[0085] K is selected from the group consisting of —NR⁷—, —C(═O)—, and—CHR⁹—;

[0086] L is selected from the group consisting of a single bond, —C(═O),—CR¹⁰R¹¹—, —C(═O)CR¹⁰R¹¹—, —CR¹⁰R¹¹C(—O)—, CR¹⁰R¹¹C(═O)—, —HR¹⁵C—CHR¹⁶—,and —R¹⁵C═CR¹⁶;

[0087] R⁹ is selected from the group consisting of H, C₁-C₈ alkyl, C₃-C₆alkenyl, C₃-C₁₀ cycloalkyl(C₀-C₄ alkyl)-, aryl(C₀-C₄ alkyl)-, andheterocyclic(C₀-C₄ alkyl)-,

[0088]  wherein said aryl or heterocyclic groups are substituted with0-2 substituents independently selected from the group consisting ofC₁-C₄ alkyl, C₁-C₄ alkoxy, F, Cl, Br, CF₃, and NO₂;

[0089] R¹⁰ is selected from the group consisting of H, F, Cl, Br, C₁-C₆alkoxy, C₁-C₈ alkyl, C₃-C₆ alkenyl, C₃-C₁₀ cycloalkyl(C₀-C₄ alkyl)-,aryl(C₀-C₄ alkyl)-, and heterocyclic(C₀-C₄ alkyl)-, wherein said aryl orheterocyclic groups are substituted with 0-2 substituents independentlyselected from the group consisting of C₁-C₄ alkyl, C₁-C₄ alkoxy, F, Cl,Br, CF₃, CN, and NO₂;

[0090] R¹¹ is selected from the group consisting of H, F, Cl, Br, OMe,C₁-C₈ alkyl, C₃-C₆ alkenyl, C₃-C₁₀ cycloalkyl(C₀-C₄ alkyl)-, aryl(C₀-C₄alkyl)-, and heterocyclic(C₀-C₄ alkyl)-, wherein said aryl orheterocyclic groups are substituted with 0-2 substituents independentlyselected from the group consisting of C₁-C₄ alkyl, C₁-C₄ alkoxy, F, Cl,Br, CF₃, CN, and NO₂;

[0091] alternatively, R¹⁰ and R¹¹, when on the same carbon atom [as in(—CR¹⁰R¹¹—)], can be taken together with the carbon atoms to which theyare attached to form a 3-7 membered carbocyclic or 3-7 memberedheterocyclic non-aromatic ring system, said carbocyclic or heterocyclicring being optionally substituted with 0-2 substituents independentlyselected from the group consisting of C₁-C₄ alkyl, C₁-C₄ alkoxy, hydroxyC₀-C₄ alkyl, oxo, F, Cl, Br, CF₃, and NO₂;

[0092] X is selected from the group consisting of OR¹², NR¹²R¹³, C₁-C₈alkyl C₃-C₆ alkenyl, C₃-C₁₀ cycloalkyl(C₀-C₄ alkyl)-, C₆-C₁₀ aryl(C₀-C₄alkyl)-, and heterocyclic(C₀-C₄ alkyl)-,

[0093]  wherein said aryl or heterocyclic groups are substituted with0-3 substituents independently selected from R¹⁴, with the proviso thatwhen L is a single bond, X cannot be NR¹²R¹³;

[0094] R¹² is selected from the group consisting of H, C₁-C₈ alkyl,C₃-C₆ alkenyl, C₃-C₁₀ cycloalkyl(C₀-C₄ alkyl)-, monocyclic or bicyclicaryl(C₀-C₄ alkyl)-, and monocyclic or bicyclic 5-10 memberedheterocyclic(C₀-C₄ alkyl)-, and —CZ¹Z²Z³,

[0095]  wherein said aryl or heterocyclic groups are substituted with0-3 substituents independently selected from R¹⁴;

[0096] Z¹ is selected from the group consisting of C₁-C₈ alkyl, C₂-C₆alkenyl, C₂-C₆ alkynyl, C₁-C₆ hydroxyalkyl, C₁-C₄ alkoxy C₁-C₄ alkyl,aryl(C₀-C₄ alkyl)-, and 4-10 membered heterocyclic (C₀-C₄ alkyl)-,

[0097]  wherein said aryl or heterocyclic groups are substituted with0-3 substituents independently selected from R¹⁴;

[0098] Z² is selected from the group consisting of C₁-C₈ alkyl, C₂-C₆alkenyl, C₂-C₆ alkynyl, C₁-C₆ hydroxyalkyl, C₁-C₄ alkoxy C₁-C₄ alkyl,C₁-C₆ NR¹⁷R¹⁸, aryl(C₀-C₄ alkyl)-, and 4-10 membered heterocyclic (C₀-C₄alkyl)-,

[0099]  wherein said aryl or heterocyclic groups are substituted with0-3 substituents independently selected from R¹⁴;

[0100] Z³ is selected from the group consisting of C₁-C₈ alkyl,R¹⁴(C₂-C₄ alkyl)-, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₁-C₆ hydroxyalkyl,C₁-C₄ alkoxy C₁-C₄ alkyl, aryl(C₀-C₄ alkyl)-, 4-10 membered heterocyclic(C₀-C₄ alkyl)-, R¹⁷O═C(C₀-C₄ alkyl)-, R¹⁷OO═C(C₀-C₄ alkyl)-, andR¹⁷R¹⁸NO═C(C₀-C₄ alkyl)-,

[0101]  wherein said aryl or heterocyclic groups are substituted with0-3 substituents independently selected from R¹⁴;

[0102] alternatively, Z¹ and Z², when on the same carbon atom [as in(—CZ¹Z²—)], can be taken together with the carbon atoms to which theyare attached to form a 3-7 membered carbocyclic or 3-7 memberedheterocyclic non-aromatic ring system, said carbocyclic or heterocyclicring being optionally substituted with 0-2 substituents independentlyselected from R¹⁴.

[0103] R¹³ is selected from the group consisting of H, C₁-C₈ alkyl,C₃-C₆ alkenyl, C₃-C₁₀ cycloalkyl(C₀-C₄ alkyl)-, C₁-C₆ alkylcarbonyl,C₁-C₆ alkylsulfonyl, C₃-C₇ cycloalkyl(C₀-C₅ alkyl)carbonyl, C₁-C₆alkoxycarbonyl, C₃-C₇ cycloalkyl(C₀-C₅ alkoxy)carbonyl, aryl(C₀-C₄alkyl)-, aryl(C₁-C₅ alkoxy)carbonyl , arylsulfonyl, heterocyclic(C₀-C₄alkyl), heterocyclic(C₁-C₅ alkoxy)carbonyl, and heterocyclicsulfonyl,

[0104]  wherein said aryl or heterocyclic groups are substituted with0-2 substituents independently selected from the group consisting ofC₁-C₄ alkyl, C₁-C₄ alkoxy, F, Cl, Br, CF₃, CN, and NO₂;

[0105] alternatively, R¹² and R¹³, when both are on the same nitrogenatom [as in (—NR¹²R¹³)] can be taken together with the nitrogen atom towhich they are attached to form a heterocycle selected from1-aziridinyl, 1-azetidinyl, 1-piperidinyl, 1-morpholinyl,1-pyrrolidinyl, thiamorpholinyl, thiazolidinyl, and 1-piperazinyl,

[0106]  said heterocycle being optionally substituted with 0-3 groupsindependently selected from oxo, C₁-C₆ alkyl, C₃-C₇ cycloalkyl(C₀-C₄alkyl)-, C₁-C₆ alkylcarbonyl, C₃-C₇ cycloalkyl(C₀-C₅ alkyl)carbonyl,C₁-C₆ alkoxycarbonyl, C₃-C₇ cycloalkyl(C₀-C₅ alkoxy)carbonyl, aryl(C₀-C₅alkyl), heterocyclic(C₀-C₅ alkyl), aryl(C₁-C₅ alkoxy)carbonyl,heterocyclic(C₁-C₅ alkoxy)carbonyl, C₁-C₆ alkylsulfonyl arylsulfonyl andheterocyclicsulfonyl,

[0107]  wherein said aryl or heterocyclic groups are substituted with0-2 substituents independently selected from the group consisting ofCH₃—, alkoxy, F, Cl, Br, CF₃, CN, and NO₂;

[0108] R¹⁴ is selected from the group consisting of H, C₁-C₁₀ alkyl,NO₂, CF₃, CN, F, Cl, Br, C₁-C₁₀ alkylcarbonyl, haloalkyl, haloalkoxy,OH, NR⁶R⁷(C₀-C₄ alkyl)-, R⁶C(═O)O(C₀-C₄ alkyl)-, R⁶OC(═O)O(C₀-C₄alkyl)-, R⁶O(C₀-C₄ alkyl), R⁶R⁷NC(═O)O(C₀-C₄ alkyl)-, R⁶R⁷NC(═O)(C₀-C₄alkyl)-, R⁶O(CR¹⁰R¹¹)₂₋₆R⁶NC(═O)(C₀-C₄ alkyl)-,R⁶R⁷N(CR¹⁰R¹¹)₂₋₆R⁶NC(═O)(C₀-C₄ alkyl)-, R⁶O₂C(CH₂)₁₋₄O(C₀-C₄ alkyl)-,R⁶OOC(C₁-C₄ alkoxy)-, R⁶OOC(C₀-C₄ alkyl)-, R⁶C(═O)(C₀-C₄ alkyl)-,R⁶C(═O)NR⁷(C₀-C₄ alkyl)-, R⁶OC(═O)NR⁷(C₀-C₄ alkyl)-, R⁶OC(═NCN)NR⁷(C₀-C₄alkyl)-, R⁶R⁷NC(═O)NR⁸(C₀-C₄ alkyl)-, R⁶OC(═NC)NR⁷(C₀-C₄ alkyl)-,R⁶(CR¹⁰R¹¹)₁₋₄ NR⁷C═O—, R⁶O(CR¹⁰R¹¹)₁₋₄O═CR⁷N—, NR⁶R⁷(CR¹⁰R¹¹)₁₋₄C═OR⁷N—, R⁶O(CR¹⁰R¹¹)₂₋₄R⁷N—, R⁶O₂C(CR¹⁰R¹¹)₁₋₄R⁷N,R⁶R⁷N(CR¹⁰R¹¹)₂₋₄R⁷N—, R⁶R⁷NC(═NCN)NR⁷(C₀-C₄ alkyl)-,R⁶R⁷NC(═C(H)(NO₂))NR⁷(C₀-C₄ alkyl)-, R⁷R⁸NC(═NR⁷)NR⁷(C₀-C₄ alkyl)-,R⁶R⁷NSO₂NR⁸(C₀-C₄ alkyl)-, R⁶SO₂NR⁷(C₀-C₄ alkyl)-, R⁶R⁷N(C₁-C₄)CO—,R⁶R⁷N(C₂-C₆ alkyl)O—, R⁶CO(CR¹⁰R¹¹)₀₋₂ R⁷N(O₂)S(C₀-C₄ alkyl),R⁶(O₂)SR⁷NC(═O)(C₀-C₄ alkyl)-, R⁶S(C₀-C₄ alkyl)-, R⁶S(═O)(C₀-C₄ alkyl)-,R⁶SO₂(C₀-C₄ alkyl)-, SO₂NR⁶R⁷, SiMe₃, R⁶R⁷N(C₂-C₄ alkyl)-, R⁶R⁷N(C₂-C₄alkoxy)-, HSO₃, HONH—, R⁶ONH—, R⁸R⁷NNR⁶—, HO(COR⁶)N—, HO(R⁶O₂C)N, C₂-C₆alkenyl, C₃-C₁₀ cycloalkyl, C₃-C₁₀ cycloalkylmethyl, aryl(C₀-C₄alkyl)-,heteroaryl(C₀-C₄alkyl)-, aryl(C₀-C₄alkyl)O—, andheteroaryl(C₀)-C₄alkyl)O—,

[0109]  wherein said aryl groups are substituted with 0-2 substituentsindependently selected from a group consisting of C₁-C₄ alkyl, C₁-C₄alkoxy, F, Cl, Br, CF₃, and NO₂;

[0110] R¹ is selected from the group consisting of H, halo, cyano, C₁-C₈alkyl, C₃-C₆ alkenyl, and C₃-C₁₀ cycloalkyl(C₀-C₄ alkyl)-, aryl(C₀-C₄alkyl)-, and heterocyclic(C₀-C₄ alkyl)-,

[0111]  wherein said aryl or heterocyclic groups are substituted with0-2 substituents independently selected from R¹⁴;

[0112] R¹⁶ is selected from the group consisting of H, halo, cyano,C₁-C₈ alkyl, C₃-C₆ alkenyl, C₃-C₁₀ cycloalkyl(C₀-C₄ alkyl)-, aryl(C₀-C₄alkyl)-, and heterocyclic(C₀-C₄ alkyl)-,

[0113]  wherein said aryl or heterocyclic groups are substituted with0-2 substituents independently selected from R¹⁴;

[0114] alternatively, when R¹⁵ and R¹⁶ are on adjacent carbon atoms [asin —HR¹⁵C—CHR¹⁶—], or when R¹⁵ and R¹⁶ are oriented on the same side ofthe double bond [as in the following structure (III)

[0115]  R¹⁵ and R¹⁶ can be taken together with the carbon atoms to whichthey are attached to form a 3-7 membered carbocyclic aromatic ornonaromatic ring system, or a 3-7 membered heterocyclic aromatic ornonaromatic ring system, said carbocyclic or heterocyclic ring beingoptionally substituted with 0-2 substituents independently selected fromthe group consisting of C₁-C₄ alkyl, C₁-C₄ alkoxy, F, Cl, Br, CF₃, NO₂.

[0116] R¹⁷ is selected from the group consisting of H, C₁-C₈ alkyl,C₃-C₆ alkenyl, C₃-C₁₀ cycloalkyl(C₀-C₄ alkyl)-, C₁-C₆ alkylcarbonyl,C₁-C₆ alkylsulfonyl, C₃-C₇ cycloalkyl(C₀-C₅ alkyl)carbonyl, C₁-C₆alkoxycarbonyl, C₃-C₇ cycloalkyl(C₀-C₅ alkoxy)carbonyl,hydroxy(C₂-C₄)alkyl-, C₁-C₃ alkoxy(C₂-C₄)alkyl-, (C₀-C₄ alkyl)(C₀-C₄alkyl) amino(C₂-C₄)alkyl-, aryl(C₀-C₄ alkyl)-, aryl(C₁-C₅alkoxy)carbonyl, arylsulfonyl, heterocyclic(C₀-C₄ alkyl),heterocyclic(C₁-C₅ alkoxy)carbonyl, and heterocyclicsulfonyl,

[0117]  wherein said aryl or heterocyclic groups are substituted with0-2 substituents independently selected from the group consisting ofC₁-C₄ alkyl, C₁-C₄ alkoxy, C₁-C₄ alkoxy C₁-C₄ alkyl, oxo, F, Cl, Br,CF₃, CN, and NO₂;

[0118] R¹⁸ is selected from the group consisting of H, C₁-C₈ alkyl,C₃-C₆ alkenyl, C₃-C₁₀ cycloalkyl(C₀-C₄ alkyl)-, aryl(C₀-C₄ alkyl)-, andheterocyclic(C₀-C₄ alkyl),

[0119]  wherein said aryl or heterocyclic groups are substituted with0-2 substituents independently selected from the group consisting ofC₁-C₄ alkyl, C₁-C₄ alkoxy, F, Cl, Br, CF₃, CN, and NO₂; and

[0120] alternatively, R¹⁷ and R¹⁸, when both are on the same nitrogenatom [as in (—NR¹²R¹³)] can be taken together with the nitrogen atom towhich they are attached to form a heterocycle selected froml-aziridinyl, 1-azetidinyl, 1-piperidinyl, 1-morpholinyl,1-pyrrolidinyl, thiamorpholinyl, thiazolidinyl, and 1-piperazinyl,

[0121]  said heterocycle being optionally substituted with 0-3 groupsselected from oxo, C₁-C₆ alkyl, C₃-C₇ cycloalkyl(C₀-C₄ alkyl)-, C₁-C₆alkylcarbonyl, (C₁-C₆ alkylcarbonyl)(C₀-C₄alkyl)amino-, C₃-C₇cycloalkyl(C₀-C₅ alkyl)carbonyl, C₁-C₆ alkoxycarbonyl, C₃-C₇cycloalkyl(C₀-C₅ alkoxy)carbonyl, aryl(C₀-C₅ alkyl), heterocyclic(C₀-C₅alkyl), aryl(C₁-C₅ alkoxy)carbonyl, heterocyclic(C₁-C₅ alkoxy)carbonyl,C₁-C₆ alkylsulfonyl arylsulfonyl and heterocyclicsulfonyl,

[0122]  wherein said aryl or heterocyclic groups are substituted with0-2 substituents independently selected from the group consisting ofCH₃—, alkoxy, F, Cl, Br, CF₃, CN, and NO₂.

[0123] Preferred are compounds of Formula I, including stereoisomericforms thereof, tautomeric forms thereof, pharmaceutically acceptablesalt forms thereof, or prodrug forms thereof,

[0124] wherein:

[0125] Z is either a 5, 6 or 7 membered monocyclic ring systemsubstituted with R³ or R⁴ and optionally substituted with 0-4substituents chosen from R¹ or R², or a 9 or 10 membered bicyclic ringsystem optionally substituted with 0-5 substituents chosen from R¹, R²,R³ or R⁴, said ring systems optionally contain up to 4 heteroatomsselected from N, O, and S, and wherein a CH₂ adjacent to any of the saidN, O or S heteroatoms is optionally substituted with oxo (═O);

[0126] R³ is a 5- or 6-membered heterocyclic ring system containing upto 4 heteroatoms selected from N, O, and S, said heterocyclic ringsystem being optionally substituted with 0-1 R⁵, wherein when R⁵ ishydroxy the heterocycle may undergo tautomerization to an oxo species ormay exist as an equilibrium mixture of both tautomers;

[0127] J and K are taken together to be selected from: —NHC(═O)—,—NHCHR⁹—, and —C(═O)NH—;

[0128] X is selected from the group consisting of OR¹², NR¹²R¹³, C₃-C₁₀cycloalkyl(C₀-C₄ alkyl)-, C₆-C₁₀ aryl(C₀-C₄ alkyl)-, andheterocyclic(C₀-C₄ alkyl)-,

[0129]  wherein said aryl or heterocyclic groups are substituted with0-3 substituents independently selected from R¹⁴, with the proviso thatwhen L is a single bond, X cannot be NR¹²R¹³;

[0130] R¹² is selected from the group consisting of ethyl, C₃-C₁₀cycloalkyl(C₀-C₄ alkyl)-, monocyclic or bicyclic aryl(C₀-C₄ alkyl)-, andmonocyclic or bicyclic 5-10 membered heterocyclic(C₀-C₄ alkyl)-, and—CZ¹Z²Z³,

[0131]  wherein said aryl or heterocyclic groups are substituted with0-3 substituents independently selected from R¹⁴;

[0132] and all other constituents are as previously described.

[0133] All references cited herein are incorporated by reference intheir entirety.

[0134] In the description above and elsewhere in the specification,including the claims, each occurrence of a particular constituent isindependent of each other occurrence of that same constituent.

[0135] Listed below are definitions of various terms used in thespecification and claims to describe the present invention.

[0136] The term “alkyl” refers to straight or branched chain alkyl.

[0137] The term “C_(integer)-C_(integer)” refers to a variable number ofcarbon atoms in a group depending on the integer values, as inC₀-C₄alkyl, which is meant to indicate a straight or branched alkylgroup containing 0-4 carbon atoms. A group with 0 (zero) carbon atomsindicates that the carbon atom is absent i.e. there is a direct bondconnecting adjacent terms. For example the term “C₀-C₄ alkylhydroxy” inthe case “C₀” is meant to indicate the group hydroxy.

[0138] The term “halogen” or “halo” refers to fluorine, chlorine,bromine or iodine.

[0139] The term “aryl” refers to monocyclic or bicyclic aromatichydrocarbons having 6 to 12 carbon atoms in the ring portion, such asphenyl, naphthyl, biphenyl and diphenyl groups which may be optionallysubstituted.

[0140] The term “alkenyl” refers to straight or branched chain alkenylgroups.

[0141] The term “alkynyl” refers to straight or branched chain alkynyl.

[0142] The term “cycloalkyl” refers to an optionally substituted,saturated cyclic hydrocarbon ring system.

[0143] The term “monocyclic” or bicyclic” refers to either a“carbocyclic” or a “heterocyclic” ring system.

[0144] The term “carbocyclic” refer to an optionally substituted, fullysaturated or unsaturated, aromatic or nonaromatic cyclic group, which isa 3 to 7 membered monocyclic, or a 7 to 11 membered bicyclic, and allthe atoms in the ring are carbon atoms. Exemplary groups include phenyl,naphthyl, anthracenyl, cyclohexyl, cyclohexenyl and the like.

[0145] The terms “heterocycle” and “heterocyclic” refer to an optionallysubstituted, fully saturated or unsaturated, aromatic or nonaromaticcyclic group, which is a 3 to 7 membered monocyclic, or a 7 to 11membered bicyclic, which have at least one heteroatom and at least onecarbon atom in the ring. Each heterocyclic ring may contain 1, 2, 3, or4 heteroatoms selected from nitrogen, oxygen and sulfur, where thenitrogen and sulfur heteroatoms may also optionally be oxidized and thenitrogen heteroatoms may also optionally be quaternized. Theheterocyclic group may be attached via a nitrogen or carbon atom.

[0146] Exemplary monocyclic heterocyclic groups include pyrrolidinyl,pyrrolyl, pyrazolyl, oxetanyl, pyrazolinyl, imidazolyl, imidazolinyl,imidazolidinyl, oxazolyl, oxazolidinyl, isoxazolinyl, isoxazolyl,thiazolyl, thiadiazolyl, thiazolidinyl, isothiazolyl, isothiazolidinyl,furanyl, tetrahydrofuranyl, thienyl, oxadiazolyl, piperidinyl,piperazinyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl,2-oxazepinyl, azepinyl, 4-piperidonyl, pyridyl, N-oxo-pyridyl,pyrazinyl, pyrimidinyl, pyridazinyl, tetrahydrothiopyranyl,tetrahydropyranyl, morpholinyl, thiamorpholinyl, thiamorpholinylsulfoxide, tetrahydrothiopyranylsulfone, thiamorpholinyl sulfone,1,3-dioxolane, tetrahydro-1,1-dioxothienyl, dioxanyl, isothiazolidinyl,thietanyl, thiiranyl, triazinyl, triazolyl, and the like.

[0147] Exemplary bicyclic heterocyclic groups include benzothiazolyl,benzoxazolyl, benzothienyl, quinuclidinyl, quinolinyl,quinolinyl-N-oxide, tetrahydroisoquinolinyl, isoquinolinyl,benzimidazolyl, benzopyranyl, indolizinyl, benzofuranyl, chromonyl,coumarinyl, cinnolinyl, quinoxalinyl, indazolyl, pyrrolopyridyl,furopyridinyl (such as furo[2,3-c]pyridinyl, furo[3,1-b]pyridinyl] orfuro[2,3-b]pyridinyl), pyrrolo[1,2-a]pyridinyl 1,3-dioxindanyl,dihydroisoindolyl, dihydroquinazolinyl (such as3,4-dihydro-4-oxo-quinazolinyl), benzisothiazolyl, benzisoxazolyl,benzodiazinyl, benzothiopyranyl, benzotriazolyl, benzpyrazolyl,dihydrobenzofuranyl, dihydrobenzothienyl, dihydrobenzothiopyranyl,dihydrobenzothiopyranyl sulfone, dihydrobenzopyranyl, indolinyl,indolyl, isochromanyl, isoindolinyl, naphthyridinyl, phthalazinyl,piperonyl, purinyl, pyridopyridyl, quinazolinyl, tetrahydroquinolinyl,thienofuryl, thienopyridyl, thienothienyl, and the like.

[0148] “IMPDH-associated disorders” refers to any disorder or diseasestate in which inhibition of the enzyme IMPDH (inosine monophosphatedehydrogenase, EC1.1.1.205, of which there are presently two knownisozymes referred to as IMPDH type 1 and IMPDH type 2) would modulatethe activity of cells (such as lymphocytes or other cells) and therebyameliorate or reduce the symptoms or modify the underlying cause(s) ofthat disorder or disease. There may or may not be present in thedisorder or disease an abnormality associated directly with the IMPDHenzyme. Examples of IMPDH-associated disorders include transplantrejection and autoimmune disorders, such as rheumatoid arthritis,multiple sclerosis, juvenile diabetes, asthma, and inflammatory boweldisease, as well as inflammatory disorders, cancer and tumor disorders,T-cell mediated hypersensitivity diseases, ischemic or reperfusioninjury, viral replication diseases, proliferative disorders and vasculardiseases.

[0149] As used herein the term “treating” includes prophylactic andtherapeutic uses, and refers to the alleviation of symptoms of aparticular disorder in a patient, the improvement of an ascertainablemeasurement associated with a particular disorder, or the prevention ofa particular immune response (such as transplant rejection). The term“patient” refers to a mammal, preferably a human.

[0150] The compounds of this invention may contain one or moreasymmetric carbon atoms and thus may occur as racemates and racemicmixtures, single enantiomers, diastereomeric mixtures and individualdiastereomers. All such isomers of the compounds disclosed herein areexpressly included within the scope of the present invention. Eachstereogenic carbon may be of the R or S configuration.

[0151] Combinations of substituents and variables thereof that result instable compounds are also contemplated within the present invention. Theterm “stable” as used herein refers to compounds which possess stabilitysufficient to allow manufacture and which maintain their integrity for asufficient period of time to be useful as a therapeutic or diagnosticagent.

[0152] As used herein, the compounds of this invention are defined toinclude pharmaceutically acceptable derivatives and prodrugs thereof. A“pharmaceutically acceptable derivative or prodrug” includes anypharmaceutically acceptable salt, ester, salt of an ester, or otherderivative of a compound of the present invention which, uponadministration to a subject, is capable of providing (directly orindirectly) a compound of the invention. Particularly favoredderivatives and prodrugs are those that increase the bioavailability ofthe compounds of the present invention when such compound isadministered to a subject (e.g., by allowing an orally administeredcompound to be more readily absorbed into the blood) or which enhancedelivery of the parent compound to a biological compartment (e.g., thebrain or lymphatic system) relative to the parent species. Preferredprodrugs include derivatives where a group that enhances aqueoussolubility or active transport through the gut membrane is appended to acompound of the present invention.

[0153] Pharmaceutically acceptable salts of the compounds disclosedherein include those derived from pharmaceutically acceptable inorganicand organic acids and bases known to those skilled in the art. Examplesof suitable acid salts include, but are not limited to, the following:acetate, adipate, alginate, aspartate, benzoate, benzenesulfonate,bisulfate, butyrate, citrate, camphorate, camphorsulfonate,cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate,formate, fumarate, glucoheptanoate, glycerophosphate, glycolate,hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide,hydroiodide, 2-hydroxyethanesulfonate, lactate, maleate, malonate,methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oxalate,palmoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate,pivalate, propionate, salicylate, succinate, sulfate, tartrate,thiocyanate, trifluoroacetic, tosylate and undecanoate. Other acids, forexample oxalic, while not in themselves pharmaceutically acceptable, maybe employed in the preparation of salts useful as intermediates inobtaining the compounds of the present invention and theirpharmaceutically acceptable acid additional salts.

[0154] Salts derived from appropriate bases include, but are not limitedto, the following: alkali metal (e.g., sodium), alkaline earth metal(e.g., magnesium), ammonium and N—(C₁₋₄ alkyl)₄ ⁺ salts. The presentinvention also envisions the quaternization of any basicnitrogen-containing groups of the compounds disclosed herein. Water- oroil-soluble or dispersible products may be obtained by suchquaternization.

Methods of Preparation

[0155] The compounds of the present invention may be synthesized usingconventional techniques known in the art. Advantageously, thesecompounds are conveniently synthesized from readily available startingmaterials. Following are general synthetic schemes for manufacturingcompounds of the present invention. These schemes are illustrative andare not meant to limit the possible techniques one skilled in the artmay use to manufacture compounds disclosed herein. Different methodswill be evident to those skilled in the art. Additionally, the varioussteps in the synthesis may be performed in an alternate sequence ororder to give the desired compound(s). All documents cited herein areincorporated herein by reference in their entirety.

[0156] Compounds of the present invention can be made by many methods,which will be known to one skilled in the art of organic chemistry. Ingeneral, the time taken to complete a reaction procedure will be judgedby the person performing the procedure, preferably with the aid ofinformation obtained by monitoring the reaction by methods such as HPLCor TLC. A reaction does not have to go to completion to be useful tothis invention. The preparation of heterocycles useful to this inventionare described in the series of books: “Comprehensive HeterocyclicChemistry. The Structure, Reactions, Synthesis and Uses, of HeterocyclicCompounds” Katritzky, A. R., Rees, C. W. Ed's Pergamon Press New York,First edition 1984, and “Comprehensive Heterocyclic Chemistry II. AReview of the Literature 1982-1995. The Structure, Reactions, Synthesisand Uses, of Heterocyclic Compounds” Katritzky, A. R., Rees, C. W. andScriven, E., F. Ed's Pergamon Press New York, 1996. In general thecompounds of this invention can be prepared by the coupling of anappropriate amine or hydrazine with a carboxylic acid to provide thecompounds of interest, alternatively the compounds may be prepared bysimple alkylation of an amine or hydrazine, or reductive alkylation ofan amine or hydrazine. Examples of methods useful for the production ofcompounds of this invention are illustrated in schemes Ia-Vb.

[0157] Amines useful for the preparation of compounds useful to thisinvention may be commercially available or readily prepared by manymethods known to one skilled in the art of organic chemistry, and aredescribed in “Comprehensive Organic Transformations. A Guide toFunctional Group Preparation.” pp-385-439. Richard C. Larock 1989 VCHPublishers, Inc. Examples include but are not limited to, reduction of anitro group, reduction of an azide and reduction of a nitrile.

[0158] A general method for the synthesis of the an amine useful in thisinvention can be perfomed by metal catalyzed cross coupling methodsknown in the literature. The simplest case is a Suzuki type crosscoupling (Miyaura, N., Yanagi, T. Suzuki, A., Synth. Comm. 11(7):513-519 (1981); A. Suzuki et. al., J. Am. Chem. Soc. 111:513 (1989);and V. N. Kalinin, Russ. Chem. Rev. 60:173 (1991)) of an aryl boronicacid or ester (Ia.1) (as shown below) with an appropriatebromoheterocycle in the presence of a suitable catalyst such astetrakis(triphenylphosphine) palladium. After the cross coupling hasbeen performed the product may be deprotected. The choice of protectinggroup and its method of removal will be readily apparent to one skilledin the art of organic chemistry. Such considerations and methods are,for example, described by Greene, Theodora W. and Wuts, Peter G. M. in“Protective Groups in Organic Synthesis.” 2nd Ed. (1991) Publisher:(John Wiley and Sons, Inc., New York, N.Y. For example, if theprotecting group is acetyl the product may be deprotected by treatmentwith aqueous potassium hydroxide at a concentration of 0.5N to 5 N atroom temperature to 100° C. for a period between 0.5 h and 24 h.

[0159] For example aryl boronic acid (Ia.5) may react with the known5-bromothiazole (Ia.6) in the presence of tetrakis(triphenylphosphine)palladium (0), to provide (Ia.7) which may be deprotected by anappropriate method.

[0160] Copper has been recently been shown to be an effective catalystfor cross coupling of aryl boronic acids to N-unsubstituted heterocyclesas described by Chan. et al., Tetrahed. Lett. 39:2933-2936 (1998); andLam et al., Tetrahed. Lett. 39:2941-2944 (1998). This results incompounds in which the heterocycle is attached to the aryl ring throughnitrogen rather than carbon. For example aryl boronic acid (Ia.5) mayreact with oxazolone (Ia.8) in the presence of copper (II) acetate inthe presence of an amine base such as pyridine to provide intermediate(Ia.9) which may be deprotected by an appropriate method

[0161] In general aryl boronic acids and esters, Ib.3, where X is not Bror I, may be prepared as shown in Scheme Ib, from the correspondingarylbromide (Ib.1) by treatment with a palladium catalyst such as[1,1′-Bis(diphenylphosphino)-ferrocene] dichloropalladium (II) andbis(pinacolato)diboron, (Ib.2), as reported by Ishayama et al., J. Org.Chem., (1995) 7508-7510. Aryl boronic esters may be converted to thecorresponding boronic acid by several methods including treatment withaqueous HCl. In a variation of the synthesis, the nitrogen may be maskedas a nitro group and later reduced by several means including metalreductions, such as by treatment with tin chloride in HCl or byrefluxing the nitro compound with zinc in the presence of CaCl₂ in asolvent such as ethanol, or in certain cases the nitro group may bereduced by catalytic hydrogenation in the presence of catalysts such aspalladium on carbon. The conditions for the reduction of nitro groupsare detailed in several references including Hudlicky, M., “Reductionsin Organic Chemistry”, 2nd Ed., ACS Monograph 188, 1996, pp 91-101American Chemical Society, Washington, D.C. A second variation of thesynthesis allows the aryl bromide to remain through the entire synthesisand elaborated to the boronic acid at the end. This may eliminate theneed for a protecting group.

[0162] In certain cases it may be more expedient to construct theheterocyclic ring by other methods. A general method for the synthesisof 5-membered heterocycles includes the 1,3-dipolar cycloadditionreaction, which is well known to one skilled in the art of organicchemistry and is described by Padwa, Albert; Editor. in “1,3-DipolarCycloaddition Chemistry, Vol. 2” (1984) John Wiley and Sons, New York,N.Y.; and Padwa, Albert; Editor. in “1,3-Dipolar CycloadditionChemistry, Vol. 1” (1984) John Wiley and Sons, New York, N.Y. Forexample oxazoles may be prepared by 1,3 dipolar cycloaddtion of thecorrosponding aldehyde (Ic.1) and (ptolylsulfonyl)methyl isocyanate(TOSMIC) (Ic.2) as shown in scheme Ic. The aldehyde may be commerciallyavailable or prepared from the corresponding methyl group by oxidationwith reagents such as CrO₃, MnO₂, and ammonium cerium (IV) nitrate bymethods well known to one skilled in the art of organic chemistry and isdescribed in Hudlicky, M., “Oxidations in Organic Chemistry”, ACSMonograph 186 (1990), American Chemical Society, Washington, DC. Thenitro group in intermediate (Ic.3), is reduced to an amine (Ic.4), asdiscussed above.

[0163] An alternative method of producing amines useful to thisinvention is by nucleophilic attack an an electron deficient ring systemas outlined in scheme Id. Halonitrobenzenes (Id.1), are eithercommercially available or readily prepared by methods known to oneskilled in the art of organic synthesis. Displacement with a variety ofnucleophiles produce compounds of structure (Id.2). In one exampleheating (Id.3) with a nucleophilic heterocycle such as triazole with orwithout the addition of a base provides the intermediate nitro compoundwhich may be reduced as previously describe to provide amines (Id.4).Alternatively simple organic nucleophiles such as cyanide can be reactedwith halonitrobenzene (Id.5) to provide an intermediate nitrocompoundwhich can be reduced by many methods to amine (Id.6).

[0164] Scheme IIa, IIb, IIc, depicts the coupling of the amines preparedin Scheme Ia and Ib to various acids. The acids useful in this inventionare either commercially available such as ethyl oxalyl chloride, ethylmalonyl chloride, chloroacetyl chloride, benzoyl formate or indol-2-ylcarboxylic acid, or readily prepared by one skilled in the art oforganic chemistry. Carboxylic acids may also be prepared by thehydrolysis of carbocylic acid esters. The coupling is carried out usingany of the many methods for the formation of amide bonds known to oneskilled in the art of organic synthesis. These methods include but arenot limited to conversion of the acid to the corresponding acidchloride, or use of standard coupling procedures such as the azidemethod, mixed carbonic acid anhydride (isobutyl chloroformate) method,carbodiimide (dicyclohexylcarbodiimide, diisopropylcarbodiimide, orwater-soluble carbodiimides) method, active ester (p-nitrophenyl ester,N-hydroxysuccinic imido ester) method, carbonyldiimidazole method,phosphorus reagents such as BOP-Cl. Some of these methods (especiallythe carbodiimide) can be enhanced by the addition of1-hydroxybenzotriazole.

[0165] Thus amine (IIa.1) may be coupled with acid chloride (IIa.2) inthe presence of an amine base such as triethylamine to produce amide(IIa.3). Ester (IIa.3) is also a useful intermediate. The ester may behydrolized by treatment with aqueous base such as sodium hydroxide toproduce acid (IIa.4). This acid can be coupled with a second amine toproduce the bisamide (IIa.5). The amines useful to this invention arecommercially available, or are readily prepared from commercial startingmaterials by one skilled in the art of organic chemistry.

[0166] In the case of carboxylic acid derivatives which contain an□-halo atom, such as chlorine or bromine, the product may be used as anintermediate. Such reagents readily react with amines in the presence ofa suitable base to provide □-aminoacids useful to this invention. Forexample in Scheme IIb, amine (IIb.1) is coupled with chloroacetylchloride, (IIb.2), to produce intermediate (IIb.3) which can be heatedin the presence of an amine with or without the addition of a base toprovide compound (IIb.4).

[0167] Scheme IIc depicts the coupling of the amine to a heterocyclicacid. This can be accomplished with many of the coupling agentsdescribed previously. The heterocyclic carboxylic acids are eithercommercially available or readily prepared by methods known to oneskilled in the art of organic chemistry. For example many heterocyclesundergo regioselective lithiation; this intermediate may be treated withCO₂ gas or solid to provide the required carboxylic acids. For exampleamine (IIc.1), may be coupled with acid (IIc.2) to provide the desiredproduct (IIc.3).

[0168] Carboxylic acid derivative useful for this invention are eithercommercially available or readily prepared by one skilled in the art oforganic chemistry. The preparation of carboxylic acids and relatedfunctional groups such as carboxylic acid esters are described in“Comprehensive Organic Transformations. A Guide to Functional GroupPreparation.” Richard C. Larock 1989 VCH Publishers, Inc. Carboxylicacids can be prepared by a number of methods not limited to ozonolysisof an alkene, ozonolysis of a furan ring, oxidation of a alkyl groupwhen attached to an aryl ring, oxidation of a primary alcohol,hydrolysis of a nitrile, carbonylation procedures, and homologation ordegradation of an existing carboxylic acid.

[0169] Scheme IIIa illustrates the preparation of a carboxylic acidderivative useful as an intermediate for this invention. The preparationof methyl 4-formyl-3-methoxybenzoate (IIIa.1) has been reported byGriera, R. et al. in European Journal of Medicinal Chemistry (1997) pp547-570. Reaction of the aldehyde with TOSMIC as described in scheme Ic,followed by acidification precipitates the desired acid.

[0170] Hydrazines useful as intermediates in this invention are eithercommercially available or may be prepared by many methods known to oneskilled in the art of organic synthesis including reduction of diazoniumsalts as illustrated in scheme IVa.

[0171] Aldehydes and ketones useful as intermediates in this inventionare either commercially available or may be readily prepared by by manymethods known to one skilled in the art of organic synthesis and areillustrated in “Comprehensive Organic Transformations. A Guide toFunctional Group Preparation.” Richard C. Larock 1989 VCH Publishers,Inc. Examples of methods for production of aldehydes include but are notlimited to oxidation of a primary alcohol, reduction of carboxylic acidester, or ozonolysis of an alkene. Examples of methods for production ofketones include but are not limited to oxidation of secondary alcohols,and oxidative cleavage of alkenes.

[0172] Compounds useful to this invention may also be prepared byreductive amination using either amines or hydrazines and an aldehyde. Auseful method of performing reductive aminations has been described byAbdel-Magid, A. F., et al in Journal of Organic Chemistry (1996) pp3849-3862. This method involves dissolving the aldehyde or ketone and anamine or hydrazine in a suitable solvent such as 1,2-dichloroethane inthe presence of sodium triacetoxyborohydride. Reductive amination isillustrated in scheme Va.

[0173] Scheme Vb illustrates alkylation as a means of forming thenitrogen carbon bond. Amine (Iic.1) may be readily alkylated by□-haloamides, by heating in a solvent such as N,N-dimethylformamide withor without the addition of a base such as potassium carbonate to providecompounds of type (Vb.1). Alkylation of amine (Iic.1) with an allylichalide in a solvent such as N,N-dimethylformamide in the presence orabsence of a base provides the alkylated compounds (Vb.2) The reactionsillustrated in scheme Vb, generally require purification by a methodsuch as flash column chromatogaphy or prepraratory high performanceliquid chormatography (HPLC) to provide the desired product. Suchmethods would be known to one skilled in the art of organic chemistry.

Utility

[0174] The compounds of the present invention inhibit IMPDH enzyme, andare thus useful in the treatment, including prevention and therapy, ofdisorders which are mediated or effected by cells which are sensitive toIMPDH inhibition, as described previously. The present invention thusprovides methods for the treatment of IMPDH-associated disorders,comprising the step of administering to a subject in need thereof atleast one compound of the formula I, in an amount effective therefor.Other therapeutic agents, such as those described below, may be employedwith the inventive compounds in the present methods. In the methods ofthe present invention, such other therapeutic agent(s) may beadministered prior to, simultaneously with or following theadministration of the compound(s) of the present invention.

[0175] Use of the compounds of the present invention in treatingexemplified by, but is not limited to, treating a range of disorderssuch as: treatment of transplant rejection (e.g., kidney, liver, heart,lung, pancreas (e.g., islet cells), bone marrow, cornea, small bowel,skin allografts, skin homografts (such as employed in burn treatment),heart valve xenografts, serum sickness, and graft vs. host disease, inthe treatment of autoimmune diseases, such as rheumatoid arthritis,psoriatic arthritis, multiple sclerosis, juvenile diabetes, asthma,inflammatory bowel disease (such as Crohn's disease and ulcerativecolitus), pyoderma gangrenum, lupus (systemic lupus erythematosis),myasthenia gravis, psoriasis, dermatitis, dernatomyositis; eczema,seborrhoea, pulmonary inflammation, eye uveitis, hepatitis, Grave'sdisease, Hashimoto's thyroiditis, autoimmune thyroiditis, Behcet's orSjorgen's syndrome (dry eyes/mouth), pernicious or immunohaemolyticanaemia, Addison's disease (autoimmune disease of the adrenal glands),idiopathic adrenal insufficiency, autoimmune polyglandular disease (alsoknown as autoimmune polyglandular syndrome), glomerulonephritis,scleroderma, morphea, lichen planus, viteligo (depigmentation of theskin), alopecia areata, autoimmune alopecia, autoimmune hypopituatarism,Guillain-Barre syndrome, and alveolitis; in the treatment of T-cellmediated hypersensitivity diseases, including contact hypersensitivity,delayed-type hypersensitivity, contact dermatitis (including that due topoison ivy), uticaria, skin allergies, respiratory allergies (hayfever,allergic rhinitis) and gluten-sensitive enteropathy (Celiac disease); inthe treatment of inflammatory diseases such as osteoarthritis, acutepancreatitis, chronic pancreatitis, asthma, acute respiratory distresssyndrome, Sezary's syndrome and vascular diseases which have aninflammatory and or a proliferatory component such as restenosis,stenosis and artherosclerosis; in the treatment of cancer and tumordisorders, such as solid tumors, lymphomas and leukemia; in thetreatment of fungal infections such as mycosis fungoides; in protectionfrom ischemic or reperfusion injury such as ischemic or reperfusioninjury that may have been incurred during organ transplantation,myocardial infarction, stroke or other causes; in the treatment of DNAor RNA viral replication diseases, such herpes simplex type 1 (HSV-1),herpes simplex type 2 (HSV-2), hepatitis (including hepatitis B andhepatitis C) cytomegalovirus, Epstein-Barr, and human immunodeficiencyvirus (HIV).

[0176] Additionally, IMPDH is also known to be present in bacteria andthus may regulate bacterial growth. As such, the IMPDH-inhibitorcompounds of the present invention may be useful in treatment orprevention of bacterial infection, alone or in combination with otherantibiotic agents.

[0177] In a particular embodiment, the compounds of the presentinvention are useful for the treatment of the aforementioned exemplarydisorders irrespective of their etiology, for example, for the treatmentof transplant rejection, rheumatoid arthritis, inflammatory boweldisease, and viral infections.

[0178] The present invention also provides pharmaceutical compositionscomprising at least one of the compounds of formula I, or a saltthereof, capable of treating an IMPDH-associated disorder in an amounteffective therefor, alone or in combination with at least one additionaltherapeutic agent, and any pharmaceutically acceptable carrier, adjuvantor vehicle. “Additional therapeutic agents” encompasses, but is notlimited to, an agent or agents selected from the group consisting of animmunosuppressant, an anti-cancer agent, an anti-viral agent, ananti-inflammatory agent, an anti-fungal agent, an antibiotic, or ananti-vascular hyperproliferation compound.

[0179] The term “pharmaceutically acceptable carrier, adjuvant orvehicle” refers to a carrier, adjuvant or vehicle that may beadministered to a subject, together with a compound of the presentinvention, and which does not destroy the pharmacological activitythereof. Pharmaceutically acceptable carriers, adjuvants and vehiclesthat may be used in the pharmaceutical compositions of the presentinvention include, but are not limited to, the following: ionexchangers, alumina, aluminum stearate, lecithin, self-emulsifying drugdelivery systems (“SEDDS”) such as d(-tocopherol polyethyleneglycol 1000succinate), surfactants used in pharmaceutical dosage forms such asTweens or other similar polymeric delivery matrices, serum proteins suchas human serum albumin, buffer substances such as phosphates, glycine,sorbic acid, potassium sorbate, partial glyceride mixtures of saturatedvegetable fatty acids, water, salts or electrolytes such as protaminesulfate, disodium hydrogen phosphate, potassium hydrogen phosphate,sodium chloride, zinc salts, colloidal silica, magnesium trisilicate,polyvinyl pyrrolidone, cellulose-based substances, polyethylene glycol,sodium carboxymethylcellulose, polyacrylates, waxes,polyethylenepolyoxypropylene-block polymers, polyethylene glycol andwool fat. Cyclodextrins such as α-, β- and γ-cyclodextrin, or chemicallymodified derivatives such as hydroxyalkylcyclodextrins, including 2- and3-hydroxypropyl-β-cyclodextrins, or other solubilized derivatives mayalso be used to enhance delivery of the compounds of the presentinvention.

[0180] The compositions of the present invention may contain othertherapeutic agents as described below, and may be formulated, forexample, by employing conventional solid or liquid vehicles or diluents,as well as pharmaceutical additives of a type appropriate to the mode ofdesired administration (for example, excipients, binders, preservatives,stabilizers, flavors, etc.) according to techniques such as those wellknown in the art of pharmaceutical formulation.

[0181] The compounds of the formula I may be administered by anysuitable means, for example, orally, such as in the form of tablets,capsules, granules or powders; sublingually; buccally; parenterally,such as by subcutaneous, intravenous, intramuscular, or intrasternalinjection or infusion techniques (e.g., as sterile injectable aqueous ornon-aqueous solutions or suspensions); nasally such as by inhalationspray; topically, such as in the form of a cream or ointment; orrectally such as in the form of suppositories; in dosage unitformulations containing non-toxic, pharmaceutically acceptable vehiclesor diluents. The present compounds may, for example, be administered ina form suitable for immediate release or extended release. Immediaterelease or extended release may be achieved by the use of suitablepharmaceutical compositions comprising the present compounds, or,particularly in the case of extended release, by the use of devices suchas subcutaneous implants or osmotic pumps. The present compounds mayalso be administered liposomally.

[0182] Exemplary compositions for oral administration includesuspensions which may contain, for example, microcrystalline cellulosefor imparting bulk, alginic acid or sodium alginate as a suspendingagent, methylcellulose as a viscosity enhancer, and sweeteners orflavoring agents such as those known in the art; and immediate releasetablets which may contain, for example, microcrystalline cellulose,dicalcium phosphate, starch, magnesium stearate and/or lactose and/orother excipients, binders, extenders, disintegrants, diluents andlubricants such as those known in the art. The present compounds mayalso be delivered through the oral cavity by sublingual and/or buccaladministration. Molded tablets, compressed tablets or freeze-driedtablets are exemplary forms which may be used. Exemplary compositionsinclude those formulating the present compound(s) with fast dissolvingdiluents such as mannitol, lactose, sucrose and/or cyclodextrins. Alsoincluded in such formulations may be high molecular weight excipientssuch as celluloses (avicel) or polyethylene glycols (PEG). Suchformulations may also include an excipient to aid mucosal adhesion suchas hydroxy propyl cellulose (HPC), hydroxy propyl methyl cellulose(HPMC), sodium carboxy methyl cellulose (SCMC), maleic anhydridecopolymer (e.g., Gantrez), and agents to control release such aspolyacrylic copolymer (e.g., Carbopol 934). Lubricants, glidants,flavors, coloring agents and stabilizers may also be added for ease offabrication and use.

[0183] Exemplary compositions for nasal aerosol or inhalationadministration include solutions in saline which may contain, forexample, benzyl alcohol or other suitable preservatives, absorptionpromoters to enhance bioavailability, and/or other solubilizing ordispersing agents such as those known in the art.

[0184] Exemplary compositions for parenteral administration includeinjectable solutions or suspensions which may contain, for example,suitable non-toxic, parenterally acceptable diluents or solvents, suchas mannitol, 1,3-butanediol, water, Ringer's solution, an isotonicsodium chloride solution, or other suitable dispersing or wetting andsuspending agents, including synthetic mono- or diglycerides, and fattyacids, including oleic acid. The term “parenteral” as used hereinincludes subcutaneous, intracutaneous, intravenous, intramuscular,intraarticular, intraarterial, intrasynovial, intrasternal, intrathecal,intralesional and intracranial injection or infusion techniques.

[0185] Exemplary compositions for rectal administration includesuppositories which may contain, for example, a suitable non-irritatingexcipient, such as cocoa butter, synthetic glyceride esters orpolyethylene glycols, which are solid at ordinary temperatures, butliquify and/or dissolve in the rectal cavity to release the drug.

[0186] Exemplary compositions for topical administration include atopical carrier such as Plastibase (mineral oil gelled withpolyethylene).

[0187] The effective amount of a compound of the present invention maybe determined by one of ordinary skill in the art, and includesexemplary dosage amounts for an adult human of from about 0.1 to 500mg/kg of body weight of active compound per day, which may beadministered in a single dose or in the form of individual divideddoses, such as from 1 to 5 times per day. It will be understood that thespecific dose level and frequency of dosage for any particular subjectmay be varied and will depend upon a variety of factors including theactivity of the specific compound employed, the metabolic stability andlength of action of that compound, the species, age, body weight,general health, sex and diet of the subject, the mode and time ofadministration, rate of excretion, drug combination, and severity of theparticular condition. Preferred subjects for treatment include animals,most preferably mammalian species such as humans, and domestic animalssuch as dogs, cats and the like, subject to IMPDH-associated disorders.

[0188] The compounds of the present invention may be employed alone orin combination with each other and/or other suitable therapeutic agentsuseful in the treatment of IMPDH-associated disorders, such as IMPDHinhibitors other than those of the present invention,immunosuppressants, anti-cancer agents, anti-viral agents,anti-inflammatory agents, anti-fungal agents, antibiotics, oranti-vascular hyperproliferation agents.

[0189] Exemplary such other therapeutic agents include the following:cyclosporins (e.g., cyclosporin A), CTLA4-Ig, antibodies such asanti-ICAM-3, anti-IL-2 receptor (Anti-Tac), anti-CD45RB, anti-CD2,anti-CD3 (OKT-3), anti-CD4, anti-CD80, anti-CD86, monoclonal antibodyOKT3, agents blocking the interaction between CD40 and CD154 (a.k.a.“gp39”), such as antibodies specific for CD40 and/or CD154, fusionproteins constructed from CD40 and/or CD154/gp39 (e.g., CD40Ig andCD8gp39), inhibitors, such as nuclear translocation inhibitors, ofNF-kappa B function, such as deoxyspergualin (DSG), non-steroidalantiinflammatory drugs (NSAIDs) such as ibuprofen, celecoxib androfecoxib, steroids such as prednisone or dexamethasone, gold compounds,antiviral agents such as abacavir, antiproliferative agents such asmethotrexate, leflunomide, FK506 (tacrolimus, Prograf), cytotoxic drugssuch as azathiprine and cyclophosphamide, TNF-α inhibitors such astenidap, anti-TNF antibodies or soluble TNF receptor, and rapamycin(sirolimus or Rapamune) or derivatives thereof.

[0190] The above other therapeutic agents, when employed in combinationwith the compounds of the present invention, may be used, for example,in those amounts indicated in the Physicians' Desk Reference (PDR) or asotherwise determined by one of ordinary skill in the art.

[0191] The compounds disclosed herein are capable of targeting andinhibiting IMPDH enzyme. Inhibition can be measured by various methods,including, for example, IMP dehydrogenase HPLC assays (measuringenzymatic production of XMP and NADH from IMP and NAD) and IMPdehydrogenase spectrophotometric assays (measuring enzymatic productionof NADH from NAD). See, e.g., Montero et al., Clinica Chimica Acta238:169-178 (1995). Additional assays known in the art can be used inascertaining the degree of activity of a compound (“test compound”) asan IMPDH inhibitor. The inventors used the following assay to determinethe degree of activity of the compounds disclosed herein as IMPDHinhibitors:

[0192] Activity of IMPDH I and IMPDH II was measured following anadaptation of the method described in WO 97/40028. The reaction mixturewas prepared containing 0.1M Tris pH 8.0, 0.1 M KCl, 3 mM EDTA, 2 mMDTT, 0.4 mM IMP and 40 nM enzyme (IMPDH I or IMPDH II). The reaction wasstarted by the addition of NAD to a final concentration of 0.4 mM. Theenzymatic reaction was followed by measuring the increase in absorbanceat 340 nM that results from the formation of NADH. For the analysis ofpotential inhibitors of the enzyme, compounds were dissolved in DMSO toa final concentration of 10 mM and added to the assay mixture such thatthe final concentration of DMSO was 2.5%. The assay was carried out in a96-well plate format, with a final reaction volume of 200 □l.

[0193] The compounds disclosed herein are capable of inhibiting theenzyme IMPDH at a measurable level, under the above-described assay oran assay which can determine an effect of inhibition of the enzymeIMPDH.

[0194] The following examples illustrate preferred embodiments of thepresent invention and do not limit the scope of the present invention,which is defined in the claims. Abbreviations employed in the Examplesare defined below. Compounds of the Examples are identified by theexample and step in which they are prepared (e.g., “1A” denotes thetitle compound of Example 1A), or by the example only where the compoundis the title compound of the example (for example, “2” denotes the titlecompound of Example 2). Abbreviations Ac Acetyl AcOH Acetic acid aq.Aqueous CDI Carbonyldiimidazole Bn Benzyl Boc tert-butoxycarbonyl DMAPDimethylaminopyridine DMF dimethylformamide DMSO Dimethylsulfoxide EDC1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride EtOAc Ethylacetate Et Ethyl EtOH Ethanol h Hours i iso HPLC High pressure liquidchromatography HOAc Acetic acid THF Tetrahydrofuran Lawesson's Reagent[2,4-bis(4-methoxyphenyl)-1,3-dithia- 2,4-diphosphetane-2-4- disufide LCliquid chromatography Me Methyl MeOH Methanol min. Minutes M⁺ (M + H)⁺M⁺¹ (M + H)⁺ MS Mass spectrometry n normal Pd/C Palladium on carbon PhPhenyl Pr Propyl Ret Time Retention time rt or RT Room temperature sat.Saturated TFA Trifluoroacetic acid THF Tetrahydrofuran TOSMICTosylmethyl isocyanide YMC YMC Inc, Wilmington, NC 28403 General:

[0195] The following LC/MS conditions were utilized:

[0196] LC/MS condition A, denoted as “ret. time^(A)”: Column: YMC S5 ODSBallistic column, 4.6×50 mm; 0%B-100%B, linear gradient over 4 min at4.0 ml/min; 1 min isocratie at 100% B; Solvent A: 10% MeOH-90% H₂O-0.1%TFA; Solvent B: 90% MeOH-10% H₂O-0.1% TFA.

[0197] LC/MS condition B, denoted as “ret. time^(B)”: Column: Shimadzu4.6×50 mm Ballistic, 0%B-100%B, linear gradient over 4 min at 4.0ml/min; 1 min isocratic at 100% B. Solvent A=10% MeOH, 90% H₂O, 0.1%TFA. Solvent B=90% MeOH, 10% H₂O, 0.1% TFA.

EXAMPLE 1N-(4-Fluorophenyl)-N2-[3-methoxy-4-(5-oxazolyl)phenyl]glycinamide

[0198]

[0199] 1A. 4-Nitro-2-methoxy-(α,α-bisacetoxy)toluene

[0200] To a 5 L three necked round bottom flask equipped with amechanical stirrer was added 4-nitro-2-methoxytoluene (150.0 g, 0.8973mol), HOAc (900 mL) and Ac₂O (900 mL). The mixture was stirred andcooled to 8° C. with an acetone/ice bath. Concentrated H₂SO₄ (136 mL)was carefully added while keeping the pot temperature <19° C. Aftercooling to 0° C., CrO₃ (252.6 g, 2.526 mol, 2.815 equiv.) was addedportion-wise over 1 hour while maintaining the reaction temperaturebetween 0-10° C. After the addition, the mixture was stirred at 0° C.for 30 minutes at which time the reaction was complete. The reactionmixture was then carefully poured into ice (1.5 kg) with stirring togive a slurry. The remaining black gummy residue was rinsed with HOAc(3×100 mL), and the washes were added to the slurry. After stirring for10 minutes, the slurry was filtered. The cake was washed with water(3×400 mL) and suction dried for 17 hours to give 1A (129.0 g, 51%). ¹HNMR (CDCl₃) d 8.02 (s, 1H), 7.89 (d, J=8.4 Hz, 1H), 7.77 (s, 1H), (d,8.4 Hz, 1H), 3.98 (s, 3H), 2.16 (s, 6H).

[0201] 1B. 4-Nitro-2-methoxybenzaldehyde

[0202] To a 2 L rounded bottom flask equipped with a condenser and amechanical stirrer was placed 1A (250.7 g, 0.8851 mol), dioxane (300 mL)and concentrated HCl (60 mL). The reaction mixture was heated to refluxand stirred under N₂ for 20 hours. Water (250 mL) was added dropwisewhile maintaining the reaction mixture at reflux. After cooling to 0° C.with an ice/water bath, the resulting slurry was stirred for 30 minutesand then filtered. The cake was washed with water (4×200 mL) and suctiondried for 17 hours to give 1B (146.3 g, 91%) as yellow solid. ¹H NMR(CDCl₃) d 10.54 (s, 1H), 8.00 (d, J=8.3 Hz, 1H), 7.91 (s, 1H), 7.89 (d,J=8.3 Hz, 1H), 4.08 (s, 3H).

[0203] 1C. 5-(4-Nitro-2-methoxyphenyl)oxazole

[0204] To a 5 L three necked round bottom flask equipped with acondenser and a mechanical stirrer was placed 1B (146.3 g, 0.8076 mol),TOSMIC (157.7 g, 0.8077 mol), K₂CO₃ (116.6 g, 0.8075 mol) and MeOH (2.5L). The mixture was heated to reflux under N₂ and stirred for 3 hours.Water (1.25 L) was added drop-wise while maintaining the pot temperaturebetween 59-69° C. The resulting slurry was cooled to room temperature,and then to 5° C. with an ice-water bath. After stirring for 30 minutesat 5° C., the slurry was filtered. The resulting cake was washed withwater (3×400 mL) and dried in a vacuum oven at 45° C. for 20 hours togive 1C (148.5 g, 84%) as a yellow-reddish solid. ¹H NMR (CDCl₃) d 8.02(s, 1H), 7.97 (d, J=2 Hz, 1H), 7.95 (d, J=2 Hz, 1H), 7.86 (s, 1H), 7.78(s, 1H), 4.11 (s, 3H).

[0205] 1D. 5-(4-Amino-2-methoxyphenyl)oxazole

[0206] In a 2 L hydrogenation flask was placed 1C (130.0 g, 0.6131 mol),Pd/C (10%, 26.2 g) and absolute EtOH (1280 mL). The mixture washydrogenated at 35-45 psi H₂ until the reaction was complete. Themixture was filtered over a pad of celite (20 g) and the cake was washedwith EtOH (3×100 mL). The filtrate was concentrated to a volume of 350mL. Heptane (500 mL) was added to the resulting slurry. After stirringfor 2 hours at room temperature, the slurry was filtered. The cake waswashed with heptane (3×100 mL) and air-dried to give 80.0 g of 1D.Another 30.2 g of product was recovered from the mother liquor affordinga total yield of 95%. ¹H NMR (CDCl₃) d 7.88 (s, 1H), 7.60 (d, J=8.4 Hz,1H), 7.41 (s, 1H), 6.41 (dd, J=8.4, 2.1 Hz, 1H), 3.34 (d, J=2.1 Hz, 1H),3.98 (bs, 2H), 3.94 (s, 3H).

[0207] 1.N-(4-Fluorophenyl)-N2-[3-methoxy-4-(5-oxazolyl)phenyl]glycinamide

[0208] A solution of 1D, (101 mg, 0.53 mmol) and2-chloro-4′-fluoroacetanilide (50 mg, 0.27 mmol) in DMF (0.15 mL) washeated at 100° C. for 15 h. After the reaction had cooled, the solventwas removed under reduced pressure, and the residue was subjected topreparative HPLC to give 1 as a tan solid. LC/MS: ret. time^(A)=3.527min., MS (M+H)⁺=342.

EXAMPLE 2 N-[3-Methoxy-4-(5-oxazolyl)phenyl]-N2-phenylglycinamide

[0209]

[0210] 2A. Preparation of2-Chloro-N-[3-Methoxy-4-(5-oxazolyl)phenyl]-acetamide

[0211] To a solution of 1D (500 mg, 2.63 mmol) and triethylamine (370μL, 2.89 mmol) in dichloromethane (13.0 mL), was added chloroacetylchloride (0.23 mL, 2.89 mmol) at 0° C. The reaction mixture was stirredat 0° C. for 10 min. and then at RT for 4 h. The mixture eas dilutedwith dichloromathane, washed with water, brine, and dried over Na₂SO₄.The mixture was filtered through celite and concentrated in vacuo togive 2A as a yellow solid. LC/MS: ret. time^(A)=3.123 min., MS(M+H)⁺=267.

[0212] 2. Preparation ofN-[3-Methoxy-4-(5-oxazolyl)phenyl]-N2-phenylglycinamide

[0213] A solution of 2A (30.0 mg, 0.11 mmol) and aniline (30 μL, 0.33mmol) in DMF (0.1 mL) was heated at 100° C. for 2.5 h. After thereaction had cooled, the solvent was removed under reduced pressure, andthe residue was subjected to preparative HPLC to give 2 as a yellowsolid. LC/MS: ret. time^(A)=3.576 min., MS (M+H)⁺=324.

EXAMPLE 3N-[3-Methoxy-4-(5-oxazolyl)phenyl]-N2-(3-methylphenyl)glycinamide

[0214]

[0215] Compound 3 was prepared by a route analogous to that used for thepreparation of 2, replacing aniline with m-toluidine. LC/MS: ret.time^(A)=3.759 min., MS (M+H)⁺=338.

EXAMPLE 4 [[3-Methoxy-4-(5-oxazolyl)phenyl]amino]oxoacetic acid ethylester

[0216]

[0217] To a solution of 1D (1.0 g, 5.26 mmol) and triethylamine (806 μL,5.78 mmol) in dichloromethane (26.3 mL), was added ethyl oxalyl chloride(0.646 μL, 5.78 mmol) at 0° C. The reaction mixture was stirred at 0° C.for 10 min. and then at RT for 15 h. The mixture was diluted withdichloromethane, washed with water, brine, and dried over Na₂SO₄.Following evaporative removal of the solvent, the residue waschromtographed on silica gel, eluting with 80:1 CH₂Cl₂:MeOH to give 4 asa yellow solid. LC/MS: ret. time^(A)=3.283 min., MS (M+H)⁺=291.

EXAMPLE 5 N-[3-Methoxy-4-(5-oxazolyl)phenyl]-N′-phenylethanediamide

[0218]

[0219] 5A. Preparation of[[3-Methoxy-4-(5-oxazolyl)phenyl]amino]oxoacetic acid

[0220] To a solution of 4 (1.45 g, 4.98 mmol) in EtOH (75.0 mL) wasadded 1N NaOH (12.4 mL, 12.45 mmol) at RT. After stirring for 15 h, thereaction mixture was neutralized with 1N HCl (12.4 mL, 12.45 mmol) andthen concentrated to give 5A and NaCl. LC/MS: ret. time^(A)=2.661 min.,MS (M+H)⁺=263.

[0221] 5B. Preparation ofN-[3-Methoxy-4-(5-oxazolyl)phenyl]-N′-phenylethanediamide

[0222] A mixture of the crude product of 5A (47 mg, 0.114 mmol), aniline(10.6 mg, 0.114 mmol), BOP (72.5 mg, 0.172 mmol), and NMM (58 mg, 0.57mmol) in DMF (0.95 mL) was stirred at RT for 15 h. The mixture wasdiluted with ethyl acetate, washed with water, brine, and dried overNa₂SO₄. Following evaporative removal of the solvent, the residue wastriturated with MeOH to give 5 as a yellow solid LC/MS: ret.time^(A)=3.960 min., MS (M+H)⁺=338.

EXAMPLES 6 THROUGH 54

[0223] Compounds 6-54 were prepared from the product of 5A by a routeanalogous to that used for the preparation of 5, replacing aniline withthe required HN₂—G¹. The compounds of these examples have the structuresshown in Table 1: TABLE 1

HPLC Ret MS Ex. No —G¹ Compound name Time^(A) (min) (M + H)⁺ 6

N-[3-Methoxy-4-(5- oxazolyl)phenyl]-N′-(2- methylphenyl)ethanediamide4.076 352 7

N-[3-Methoxy-4-(5- oxazolyl)phenyl]-N′-(3- methylphenyl)ethanediamide4.162 352 8

N-[3-Methoxy-4-(5- oxazolyl)phenyl]-N′-(4- methylphenyl)ethanediamide4.181 352 9

(S)-[[3-[[[[3-Methoxy-4-(5-oxazolyl)phenyl]amino]oxoacetyl]amino]phenyl]methyl]carbamic acidtetrahydro-3-furanyl ester 3.722 481 10

N-[3-Methoxy-4-(5- oxazolyl)phenyl]-N′-(3- methoxyphenyl)ethanediamide4.141 368 11

N-[3-Methoxy-4-(5- oxazolyl)phenyl]-N′- (phenylmethyl)ethanediamide3.948 352 12

N-(4-Cyanophenyl)-N′-[3- methoxy-4-(5- oxazolyl)phenyl]ethanediamide3.843 363 13

N-(1,1-Dimethylethyl)-N′-[3- methoxy-4-(5- oxazolyl)phenyl]ethanediamide4.07 318 14

N-[1,1- Bis(hydroxymethyl)propyl]-N′- [3-methoxy-4-(5-oxazolyl)phenyl]ethanediamide 3.34 364 15

N-(2-Hydroxy-1,1- dimethylethyl)-N′-[3-methoxy-4- (5-oxazolyl)phenyl]ethanediamide 3.51 334 16

N-[[[3-Methoxy-4-(5- oxazolyl)phenyl]amino]oxoacetyl]- 2-methylalanine1,1- dimethylethyl ester 4.52 404 17

N-(2-Hydroxy-1,1- dimethylpentyl)-N′-[3-methoxy- 4-(5-oxazolyl)phenyl]ethanediamide 4.35 376 18

N-[2-[(2-Hydroxy-1,1- dimethylethyl)amino]-1,1-dimethylethyl]-N′-[3-methoxy-4- (5- oxazolyl)phenyl]ethanediamide 2.88405 19

N-[2-(Dimethylamino)-1,1- dimethylethyl]-N′-[3-methoxy-4- (5-oxazolyl)phenyl]ethanediamide 2.75 361 20

N-(1,1-Diethyl-2-propynyl)-N′- [3-methoxy-4-(5-oxazolyl)phenyl]ethanediamide 4.45 356 21

N-[3-Methoxy-4-(5- oxazolyl)phenyl]-N′-(1,1,3,3-tetramethylbutyl)ethanediamide 4.25 374 22

N-(1,1-Dimethylpropyl)-N′-[3- methoxy-4-(5-oxazolyl)phenyl]ethanediamide 4.47 332 23

N-[1- (Hydroxymethyl)cyclopentyl]- N′-[3-methoxy-4-(5-oxazolyl)phenyl]ethanediamide 3.94 360 24

N-[2-(4-Fluorophenyl)-1,1- dimethylethyl]-N′-[3-methoxy-4- (5-oxazolyl)phenyl]ethanediamide 4.82 412 25

N-[[[3-Methoxy-4-(5- oxazolyl)phenyl]amino]oxoacetyl]- α-methyltyrosinemethyl ester 3.98 454 26

N-[[[3-Methoxy-4-(5- oxazolyl)phenyl]amino]oxoacetyl]-a-methyltryptophan methyl ester 4.37 477 27

N-[1,1- Bis(hydroxymethyl)ethyl]-N′-[3- methoxy-4-(5-oxazolyl)phenyl]-N-methylethanediamide 3.02 350 28

N-(1,1-Dimethyl-3-oxobutyl)- N′-[3-methoxy-4-(5-oxazolyl)phenyl]ethanediamide 3.74 360 29

N-[3-Methoxy-4-(5- oxazolyl)phenyl]-N′-(1-methyl-1-phenylethyl)ethanediamide 4.48 380 30

N-(2-Hydroxy-1,2-dimethyl-1- phenylpropyl)-N′-[3-methoxy-4- (5-oxazolyl)phenyl]ethanediamide 4.29 424 31

N-[[[3-Methoxy-4-(5- oxazolyl)phenyl]amino]oxoacetyl]- 2-methylalaninemethyl ester 3.68 362 32

1-[[[[3-Methoxy-4-(5-oxazolyl)phenyl]amino]oxoacetyl]amino]cyclopropanecarboxylic acid methylester 2.63 360 33

N-(1-Ethynylcyclohexyl)-N′-[3- methoxy-4-(5-oxazolyl)phenyl]ethanediamide 3.55 368 34

(R)-N-[1-(Hydroxymethyl)-1- methylpropyl]-N′-[3-methoxy-4-(5-oxazolyl)phenyl]-N- methylethanediamide 2.95 348 35

N-[[[3-Methoxy-4-(5- oxazolyl)phenyl]amino]oxoacetyl]- 2-methylalanine2.60 348 36

N-[1,1-Dimethyl-2-oxo-2-(1- piperidinyl)ethyl]-N′-[3- methoxy-4-(5-oxazolyl)phenyl]ethanediamide 2.87 415 37

N-[1,1-Dimethyl-2-(4-methyl-1- piperazinyl)-2-oxoethyl]-N′-[3-methoxy-4-(5- oxazolyl)phenyl]ethanediamide 2.06 430 38

N-[1,1-Dimethyl-2-(4- morpholinyl)-2-oxoethyl]-N′-[3- methoxy-4-(5-oxazolyl)phenyl]ethanediamide 2.41 417 39

4-[2-[[[[3-Methoxy-4-(5-oxazolyl)phenyl]amino]oxoacetyl]amino]-2-methyl-1- oxopropyl]-1-piperazinecarboxylic acid ethyl ester 2.73 488 40

N-[2-[3-(Acetylmethylamino)-1- pyrrolidinyl]-1,1-dimethyl-2-oxoethyl]-N′-[3-methoxy-4-(5- oxazolyl)phenyl]ethanediamide 2.37 472 41

N-[1,1-Dimethyl-2-[methyl[2- (methylamino)ethyl]amino]-2-oxoethyl]-N′-[3-methoxy-4-(5- oxazolyl)phenyl]ethanediamide 2.05 2.05742

N-[1,1-Dimethyl-2-oxo-2- (propylamino)ethyl]-N′-[3- methoxy-4-(5-oxazolyl)phenyl]ethanediamide 2.71 389 43

N-[1,1-Dimethyl-2-[[2- (methylamino)ethyl]amino]-2-oxoethyl]-N′-[3-methoxy-4-(5- oxazolyl)phenyl]ethanediamide 2.08 404 44

N-[1,1-Dimethyl-2-[[2-(4- morpholinyl)ethyl]amino]-2-oxoethyl]-N′-[3-methoxy-4-(5- oxazolyl)phenyl]ethanediamide 2.14 460 45

N-[1,1-Dimethyl-2-oxo-2-[[3-(2- oxo-1- pyrrolidinyl)propyl]amino]ethyl]-N′-[3-methoxy-4-(5- oxazolyl)phenyl]ethanediamide 2.55 472 46

N-[2-[[2-(1H-Imidazol-4- yl)ethyl]amino]-1,1-dimethyl-2-oxoethyl]-N′-[3-methoxy-4-(5- oxazolyl)phenyl]ethanediamide 2.14 441 47

N-[2-[[2- (Acetylamino)ethyl]amino]-1,1- dimethyl-2-oxoethyl]-N′-[3-methoxy-4-(5- oxazolyl)phenyl]ethanediamide 3.09 3.09 48

N-[2-[[2-(1H-Imidazol-1- yl)ethyl]amino]-1,1-dimethyl-2-oxoethyl]-N′-[3-methoxy-4-(5- oxazolyl)phenyl]ethanediamide 2.14 441 49

N-[1,1-Dimethyl-2-oxo-2-[[2-(4- pyridinyl)ethyl]amino]ethyl]-N′-[3-methoxy-4-(5- oxazolyl)phenyl]ethanediamide 2.16 452 50

N-[1,1-Dimethyl-2-oxo-2- [[(tetrahydro-2-furanyl)methyl]amino]ethyl]-N′- [3-methoxy-4-(5-oxazolyl)phenyl]ethanediamide 2.63 431 51

N-[2-[(2-Methoxyethyl)amino]- 1,1-dimethyl-2-oxoethyl]-N′-]3-methoxy-4-(5- oxazolyl)phenyl]ethanediamide 2.47 405 52

N-[2-(Dimethylamino)-1,1- dimethyl-2-oxoethyl]-N′-[3- methoxy-4-(5-oxazolyl)phenyl]ethanediamide 1.25 375 53

N-[2-[4-(2-Methoxyethyl)-1- piperazinyl]-1,1-dimethyl-2-oxoethyl]-N′-[3-methoxy-4-(5- oxazolyl)phenyl]ethanediamide 1.22 474 54

N-[1,1-Dimethyl-2-oxo-2-(2- pyridinylamino)ethyl]-N′-[3- methoxy-4-(5-oxazolyl)phenyl]ethanediamide 1.217 1.217

EXAMPLE 55 3-[[Methoxy-4-(5-oxazoly)phenyl]amino]-3-oxopropanoic acidethyl ester

[0224]

[0225] 55 was prepared from 1D by a route analogous to that used for thepreparation of 4, replacing ethyl oxalyl chloride with ethyl malonylchloride. LC/MS: ret. time^(A)=3.169 min., MS (M+H)⁺=305.

EXAMPLE 56N-[3-Methoxy-4-(5-oxazolyl)phenyl]-N′-(3-methylphenyl)propanediamide

[0226]

[0227]

[0228] 56 A. Preparation of3-[[3-Methoxy-4-(5-oxazolyl)phenyl]amino]-3-oxopropanoic acid

[0229] 56 A was prepared from 55 by a route analogous to that used forthe preparation of 5A. LC/MS: ret. time^(A)=2.611 min., MS (M+H)⁺=277.

[0230] 56B. Preparation ofN-[3-Methoxy-4-(5-oxazolyl)phenyl]-N′-(3-methylphenyl)propanediamide

[0231] 56 was prepared from 56A by a route analogous to that used forthe preparation of 5, replacing aniline with m-toluidine. LC/MS: ret.time^(A)=3.783 min., MS (M+H)⁺=366.

EXAMPLES 57 AND 58

[0232] Compounds 57 and 58 were prepared from 56A, by a route analogousto that used for the preparation of 5, replacing aniline with therequired HN₂—G². 57 and 58 have the structures as shown below and inTable 2:

TABLE 2 HPLC Ret Ex. No —G² Compound name Time^(A) (min) MS (M + H)⁺ 57

N-[3-Methoxy-4-(5- oxazolyl)phenyl]-N′- (phenyl)propanediamide 3.562 35258

(S)-[[3-[[3-[[3- Methoxy-4-(5- oxazolyl)phenyl]amino]-1,3-dioxopropyl]amino]phenyl]methyl]carbamic acid tetra- hydro-3-furanylester 3.335 495

EXAMPLE 59 N-[3-Methoxy-4-(5-oxazolyl)phenyl]benzeneacetamide

[0233]

[0234] Compound 59 was prepared from 1D by a route analogous to thatused for the preparation of 4, replacing ethyl oxalyl chloride withphenylacetic acid. LC/MS: ret. time^(A)=3.617 min., MS (M+H)⁺=309.

EXAMPLE 60 N-[3-Methoxy-4-(5-oxazolyl)phenyl]-α-oxobenzeneacetamide

[0235]

[0236] Compound 60 was prepared from the product of 1D by a routeanalogous to that used for the preparation of 4, replacing ethyl oxalylchloride with benzoylformic acid. LC/MS: ret. time^(A)=3.843 min., MS(M+H)⁺=323.

EXAMPLE 61 N-[3-Methoxy-4-(5-oxazolyl)phenyl]-1H-indole-2-carboxamide

[0237]

[0238] To a solution of 1D (0.5 g, 2.63 mmol) was sequentially addedanhydrous dimethylformamide (8 mL), indole-2-carboxylic acid (0.42 g,2.63 mmol) and 1-(3-dimethylaminopropyl)-3(0.5 g, 2.63 mmol). Thereaction mixture was stirred for 18 hours at room temperature,concentrated under reduced pressure and partitioned between ethylacetate (50 mL) and 1N HCl (20 mL). The ethyl acetate layer issuccessively washed with 1N NaOH (20 mL), brine (20 mL), dried oversodium sulfate and concentrated to yield 61 (0.36 g, 41%). LC/MS ret.time^(A)=4.330 min.; MS (M+H)⁺=334.

EXAMPLE 62N-[3-Methoxy-4-(5-oxazolyl)phenyl]-1-methyl-1H-indole-2-carboxamide

[0239]

[0240] To a solution of 1D (30 mg, 0.158 mmol) was sequentially added1-Methylindole-2-carboxylic acid (28 mg, 0.158 mmol), BOP (100 mg, 0.237mmol), NMM (80 mg, 0.790 mmol) and anhydrous dimethylformamide (1.3 mL).The reaction mixture was stirred for 18 hours at room temperature,concentrated under reduced pressure and purified by preparative HPLC toyield 32 mg of 62. LC/MS ret time^(A)=4.177 min.; MS (M+H)⁺=348.

EXAMPLES 63-65

[0241] Compounds 63-65 were prepared from the product of 1D by a routeanalogous to that used for the preparation of 62, replacing1-Methylindole-2-carboxylic acid with the required HO(CO)—G³. Thecompounds of these examples have the structures shown in Table 3:

TABLE 3 HPLC Ret MS Ex. No —G³ Compound name time^(B) (min) (M + H)⁺ 63

N-[3-Methoxy-4-(5- oxazolyl)phenyl]-2- benzofurancarboxamide 4.023 33564

N-[3-Methoxy-4-(5- oxazolyl)phenyl]benzo[b]thiophene- 2-carboxamide4.167 351 65

N-[3-Methoxy-4-(5- oxazolyl)phenyl]-1,3- benzodioxole-5-carboxamide3.687 339

EXAMPLE 66N-[3-Methoxy-4-(5-oxazolyl)phenyl]-1-methyl-1H-pyrrole-2-carboxamide

[0242]

[0243] To a mixture of 3-methoxy-4-(5-oxazoyl)aniline 1D (0.050 g, 0.263mmol) and 1-methyl-2-pyrolecarboxylic acid (0.033 g, 0.263 mmol) in 1.0mL of dimethylformamide (0.050 g, 0.263 mmol) in a 2 dram rubber-linedscrewcap vial was added1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide-HCl. The reaction mixturewas placed in a Innova 2000 Platform Shaker equipped with a standardheat block and shaken at 200 rpm overnight at approximately 50° C.Aqueous acid (10%, 1 mL) was added, and the mixture was extracted threetimes with ethyl acetate. The organic layer was washed with a 1Nsolution of sodium hydroxide, washed with brine, and dried overanhydrous sodium sulfate. Concentration under reduced pressure afforded66 as a pale yellow solid. The product was 96% pure by analytical HPLCwith a ret. time=3.53 min. (Column: YMC S5 ODS 4.6×50 mm Ballistic;Solvent A=10% MeOH, 90% H₂O, 0.2% H₃PO₄; Solvent B=90% MeOH, 10% H₂O,0.2% H₃PO₄) and a LC/MS (M+H)⁺=298.23.

EXAMPLE 675-(1,1-Dimethylethyl)-N-[3-methoxy-4-(5-oxazolyl)phenyl]-2-furancarboxamide

[0244]

[0245] A mixture of 3-methoxy-4-(5-oxazoyl)aniline 1D (0.050 g, 0.263mmol), 5-tert-butyl-2-furoic acid (0.044 g, 0.263 mmol), and1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide-HCl (0.050 g, 0.263 mmol)in 1.0 mL of dimethylformamide was subjected to the procedure used forthe preparation of 66 to give 52.1 mg of 67 as a yellow solid. Theproduct, 67, was 95% pure by analytical HPLC with a retention time=3.82min. (Column: YMC S5 ODS 4.6×50 mm Ballistic; Solvent A=10% MeOH, 90%H₂O, 0.2% H₃PO₄; Solvent B=90% MeOH, 10% H₂O, 0.2% H₃PO₄) and a LC/MS(M+H)⁺=341.19.

EXAMPLE 68N-[3-Methoxy-4-(5-oxazolyl)phenyl]-4,5-dimethyl-2-furancarboxamide

[0246]

[0247] A mixture of 3-methoxy-4-(5-oxazoyl)aniline 1D (0.050 g, 0.263mmol), 2,3-dimethylfuran-5-carboxylic acid (0.037 g, 0.263 mmol), and1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide-HCl (0.050 g, 0.263 mmol)in 1.0 mL of dimethylformamide was subjected to the procedure used forthe preparation of 66 to give 23.0 mg of 68 as a pale yellow solid. Theproduct, 68, was 95% pure by analytical HPLC with a retention time=3.79min. (Column: YMC S5 ODS 4.6×50 mm Ballistic; Solvent A=10% MeOH, 90%H₂O, 0.2% H₃PO₄; Solvent B=90% MeOH, 10% H₂O, 0.2% H₃PO₄) and a LC/MS(M+H)⁺=319.29.

EXAMPLE 69N-[3-Methoxy-4-(5-oxazolyl)phenyl]-5-methyl-2-thiophenecarboxamide

[0248]

[0249] A mixture of 3-methoxy-4-(5-oxazoyl)aniline 1D (0.050 g, 0.263mmol), 5-methyl-2-thiophenecar acid (0.037 g, 0.263 mmol), and1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide-HCl (0.050 g, 0.263 mmol)in 1.0 mL of dimethylformamide was subjected to the procedure used forthe preparation of 66 to give 25.8 mg of 69 as a yellow solid. Theproduct, 69, was 92% pure by analytical HPLC with a retention time=3.77min. (Column: YMC S5 ODS 4.6×50 mm Ballistic; Solvent A=10% MeOH, 90%H₂O, 0.2% H₃PO₄; Solvent B=90% MeOH, 10% H₂O, 0.2% H₃PO₄) and a LC/MS(M+H)⁺=315.17.

EXAMPLE 70N-[3-Methoxy-4-(5-oxazolyl)phenyl]-5-(2-pyridinyl)-2-thiophenecarboxamide

[0250]

[0251] A mixture of 3-methoxy-4-(5-oxazoyl)aniline 1D (0.050 g, 0.263mmol), 5-(pyrid-2-yl)-thiophene-2-carboxylic acid (0.054 g, 0.263 mmol),and 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide-HCl (0.050 g, 0.263mmol) in 1.0 mL of dimethylformamide was subjected to the procedure usedfor the preparation of 66 to give 4.6 mg of 70 as a yellow solid. Theproduct, 70, was 80% pure by analytical HPLC with a retention time=3.83min. (Column: YMC S5 ODS 4.6×50 mm Ballistic; Solvent A=10% MeOH, 90%H₂O, 0.2% H₃PO₄; Solvent B=90% MeOH, 10% H₂O, 0.2% H₃PO₄) and a LC/MS(M+H)⁺=378.

EXAMPLE 71N-[3-Methoxy-4-(5-oxazolyl)phenyl]-2,4-dimethyl-5-thiazolecarboxamide

[0252]

[0253] A mixture of 3-methoxy-4-(5-oxazoyl)aniline 1D (0.050 g, 0.263mmol), 2,4-dimethylthiazole-5-carboxylic acid (0.041 g, 0.263 mmol), and1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide-HCl (0.050 g, 0.263 mmol)in 1.0 mL of dimethylformamide was subjected to the procedure used forthe preparation of 66 to give 15.0 mg of 71 as a pale yellow solid. Theproduct, 71, was 93% pure by analytical HPLC with a retention time=3.46min. (Column: YMC S5 ODS 4.6×50 mm Ballistic; Solvent A=10% MeOH, 90%H₂O, 0.2% H₃PO₄; Solvent B=90% MeOH, 10% H₂O, 0.2% H₃PO₄) and a LC/MS(M+H)⁺=330.16.

EXAMPLE 725-Hydroxy-N-[3-methoxy-4-(5-oxazolyl)phenyl]-1H-indole-2-carboxamide

[0254]

[0255] A mixture of 3-methoxy-4-(5-oxazoyl)aniline 1D (0.050 g, 0.263mmol), 5-hydroxy-2-indolecarboxylic acid (0.047 g, 0.263 mmol), and1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide-HCl (0.050 g, 0.263 mmol)in 1.0 mL of dimethylformamide was subjected to the procedure used forthe preparation of 66 to give a mixture that contained ˜45% of 72. Themixture was washed with ether (2×) to give 9.2 mg of 72 as a pale yellowsolid. The product, 72, was 96% pure by analytical HPLC with a retentiontime=3.39 min. (Column: YMC S5 ODS 4.6×50 mm Ballistic; Solvent A=10%MeOH, 90% H₂O, 0.2% H₃PO₄; Solvent B=90% MeOH, 10% H₂O, 0.2% H₃PO₄) anda LC/MS (M+H)⁺=350.20.

EXAMPLE 737-Methoxy-N-[3-methoxy-4-(5-oxazolyl)phenyl]-2-benzofurancarboxamide

[0256]

[0257] A mixture of 3-methoxy-4-(5-oxazoyl)aniline 1D (0.100 g, 0.526mmol), 7-methoxy-2-benzofurancarboxylic acid (0.101 g, 0.526 mmol), and1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide-HCl (0.101 g, 0.526 mmol)in 1.5 mL of dimethylformamide was subjected to the procedure used forthe preparation of 66 to give a crude product which was washed withether (2×) to give 78.0 mg of 73 as a pale yellow solid. The product,73, was 99% pure by analytical HPLC with a retention time=4.15 min.(Column: YMC S5 ODS 4.6×50 mm Ballistic; Solvent A=10% MeOH, 90% H₂O,0.2% H₃PO₄; Solvent B=90% MeOH, 10% H₂O, 0.2% H₃PO₄) and a LC/MS(M+H)⁺=365.20.

EXAMPLE 748-Hydroxy-N-[3-methoxy-4-(5-oxazolyl)phenyl]-2-quinolinecarboxamide

[0258]

[0259] A mixture of 3-methoxy-4-(5-oxazoyl)aniline 1D (0.050 g, 0.263mmol), 8-hydroxyquinoline-2-carboxylic acid (0.050 g, 0.263 mmol), and1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide-HCl (0.050 g, 0.263 mmol)in 1.0 mL of dimethylformamide was subjected to the procedure used forthe preparation of 66 to give 23.0 mg of 74 as a pale yellow solid. Theproduct, 74, was 93% pure by analytical HPLC with a retention time=4.22min. (Column: YMC S5 ODS 4.6×50 mm Ballistic; Solvent A=10% MeOH, 90%H₂O, 0.2% H₃PO₄; Solvent B=90% MeOH, 10% H₂O, 0.2% H₃PO₄) and a LC/MS(M+H)⁺=362.26.

EXAMPLE 75 (E)-N-[3-Methoxy-4-(5-oxazolyl)pheny]-3-phenyl-2-propenamide

[0260]

[0261] A mixture of 3-methoxy-4-(5-oxazolyl)aniline 1D (15.0 mg, 0.0789mmol), trans-cinnamic acid (17.5 mg, 0.118 mmol),1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (18.2 mg,0.949 mmol), 4-dimethylamino pyridine (9.6 mg, 0.786 mmol), indichloromethane (2 mL) and DMF (0.5 mL) was shaken in a 16×100 mm testtube for 24 h. The reaction solution was diluted with dichloromethane (4mL), and washed successively with 1N NaOH (1 mL) and 1N HCl (1 mL).Evaporation of solvent provided the desired product 75 (18.2 mg, 72%yield). Ret. Time: 4.25 min LC/MS conditions: Column: Shimadzu 4.6×50 mmBallistic. Solvent A=10% MeOH, 90% H₂O, 0.1% TFA. Solvent B=90% MeOH,10% H₂O, 0.1% TFA and a LC/MS (M+H)⁺=321.

EXAMPLES 76-99

[0262] Compound 76 through 99 were prepared from the product 1D by aroute analogous to that used for the preparation of 75, replacingtrans-cinnamic acid with the required HO(CO)—G⁴.

[0263] If the products carry acetic or basic moieties, the solvent wasevaporated under vacuum and products were purified by preparative HPLC.The compounds of these examples have the structures shown in Table 4:

TABLE 4 HPLC Ret MS Ex. No —G³ Compound name Time^(B) (min) (M + H)⁺ 76

N-[3-Methoxy-4-(5- oxazolyl)phenyl]benzamide 3.77 295 77

(E)-N-[3-Methoxy-4-(5- oxazolyl)phenyl]-3-(2-methylphenyl)-2-propenamide 4.17 335 78

(E)-N-[3-Methoxy-4-(5- oxazolyl)phenyl]-3-(4-methylphenyl)-2-propenamide 4.19 335 79

(E)-3-(2-Fluorophenyl)-N-[3- methoxy-4-(5-oxazolyl)phenyl]-2-propenamide 4.06 339 80

(E)-3-(3-Fluorophenyl)-N-[3- methoxy-4-(5-oxazolyl)phenyl]-2-propenamide 4.09 339 81

(E)-3-(4-Fluorophenyl)-N-[3- methoxy-4-(5-oxazolyl)phenyl]-2-propenamide 4.04 339 82

(E)-3-(2-Chlorophenyl)-N-[3- methoxy-4-(5-oxazolyl)phenyl]-2-propenamide 4.21 355 83

(E)-3-(3-Chlorophenyl)-N-[3- methoxy-4-(5-oxazolyl)phenyl]-2-propenamide 4.29 355 84

(E)-3-(4-Chlorophenyl)-N-[3- methoxy-4-(5-oxazolyl)phenyl]-2-propenamide 4.27 355 85

(E)-N-[3-Methoxy-4-(5- oxazolyl)phenyl]-3-[2-(trifluoromethyl)phenyl]-2- propenamide 4.21 389 86

(E)-3-(3-Cyanophenyl)-N-[3- methoxy-4-(5-oxazolyl)phenyl]- 2-propenamide3.89 346 87

(E)-3-[4-(Acetylamino)phenyl]- N-[3-methoxy-4-(5-oxazolyl)phenyl]-2-propenamide 3.76 378 88

(E)-3-(2,3-Dimethoxyphenyl)-N- [3-methoxy-4-(5-oxazolyl)phenyl]-2-propenamide 3.96 381 89

(E)-3-(2,6-Difluorophenyl)-N- [3-methoxy-4-(5-oxazolyl)phenyl]-2-propenamide 4.11 357 90

(E)-N-[3-Methoxy-4-(5- oxazolyl)phenyl]-3-(2,3,4- trimethoxyphenyl)-2-propenamide 3.97 411 91

(E)-2-Fluoro-N-[3-methoxy-4- (5-oxazolyl)phenyl]-3-phenyl-2- propenamide4.18 339 92

(E)-3-(2-Furanyl)-N-[3- methoxy-4-(5-oxazolyl)phenyl]- 2-propenamide3.73 311 93

(E)-N-[3-Methoxy-4-(5- oxazolyl)phenyl]-3-(2-thienyl)- 2-propenamide3.90 327 94

(E)-N-[3-Methoxy-4-(5- oxazolyl)phenyl]-3-(3- pyridinyl)-2-propenamide2.84 322 95

(E)-N-[3-Methoxy-4-(5- oxazolyl)phenyl]-3-(4- pyridinyl)-2-propenamide2.81 322 96

(E)-N-[3-Methoxy-4-(5- oxazolyl)phenyl]-3-(1-naphthalenyl)-2-propenamide 4.38 371 97

N-[3-Methoxy-4-(5- oxazolyl)phenyl]-3,4- dimethylbenzamide 4.04 334 98

N-[3-Methoxy-4-(5- oxazolyl)phenyl]-2- indolizinecarboxamide 3.78 334 99

(E)-N-[3-Methoxy-4-(5- oxazolyl)phenyl]-3-[3-methoxy-4-(phenylmethoxy)phenyl]-2- propenamide 4.40 457

[0264] The materials required for the synthesis of the compoundsdescribed above are commercially available. The compound below (ofExample 100) is useful as an intermediate in the preparation of 9 and58.

EXAMPLE 100 3-aminophenyl)-(+)-tetrahydrofuranylcarbamate

[0265]

[0266] 100A. Preparation of 3-Aminobenzylamine

[0267] 3-Cyanoaniline (0.50 g, 4.23 mmol) in 100 mL of MeOH was stirredovernight at room temperature under a H₂ environment in the presence of10% Pd/C (100 mg). The Pd/C was removed by filtration through a pad ofCelilte, and the resulting filtrate was concentrated under reducedpressure to give 0.516 g (˜100%) of 100A as a thick oil. The product wasused without any further purification.

[0268] 100B. Preparation of (S)-(+)-tetrahydrofuranylchloroformate

[0269] To a solution of phosgene (8 mL of a ˜20% in toluene, 17.0 mmol)in 20 mL of dichloromethane at 0° C. was added a solution of(S)-(+)-hydroxytetrahydrofuran (0.50 g, 5.67 mmol) and triethylamine(1.58 mL, 11.3 mmol) in 15 mL of dichloromethane dropwise over 20 min.The reaction mixture was stirred for 15 h at room temperature. Thesolvent was removed under reduced pressure, and the resulting residuewas dissolved in ether. The triethylamine hydrochloride salt was removedby filtration. Concentration followed by purification of the residue bysilica gel chromatography afforded 0.509 g (60%) of 100B as a clear oil.

[0270] 100C. Preparation of3-aminonhenyl)-(+)-tetrahydrofuranylcarbamate

[0271] To 100A (0.509 g, 3.38 mmol) in 15 mL of dichloromethane at 0° C.was added a solution of the product of 100B (0.517 g, 4.23 mmol) andtriethylamine (0.94 mL, 6.76 mmol) in 15 mL of dichloromethane dropwiseover 10 min. The reaction mixture was stirred overnight at roomtemperature. The solvent was removed under reduced pressure, and theresidue was dissolved in ether. The solid triethylamine hydrochloridesalt was removed by filtration. Concentration followed by purificationof the residue by silica gel chromatography afforded 0.508 g (64%) of100 as a clear oil. LC/MS: ret. time^(A)=1.07 min.; MS (M+H)⁺=237.

[0272] Although the present invention has been described in some detailby way of illustration and example for purposes of clarity andunderstanding, it will be apparent that certain changes andmodifications may be practiced within the scope of the appended claims.

We claim:
 1. A compound of the following formula I, or apharmaceutically acceptable salt thereof:

wherein: Z is a monocyclic or bicyclic ring system optionally containingup to 4 heteroatoms selected from N, O, and S, and wherein a CH₂adjacent to any of the said N, O or S heteroatoms is optionallysubstituted with oxo (═O), and wherein Z is optionally substituted with0-5 substituents chosen from R¹, R², R³ or R⁴; R¹ and R² are eachindependently selected from the group consisting of H, F, Cl, Br, I,NO₂, CF₃, CN, OCF₃, OH, C₁-C₄alkoxy-, C₁-C₄alkylcarbonyl-, C₁-C₆ alkyl,hydroxy C₁-C₄ alkyl-, C₃-C₆ alkenyl, C₃-C₆ alkynyl, C₃-C₁₀cycloalkyl(C₀-C₄alkyl)-, H₂N(C₀-C₄)alkyl-, R⁶HN(C₀-C₄)alkyl-,R⁶R⁷N(C₀-C₄)alkyl-, R⁷S(C₀-C₄)alkyl-, R⁷S(O)(C₀-C₄)alkyl-,R⁷SO₂(C₀-C₄)alkyl-, R⁶NSO₂(C₀-C₄)alkyl-, HSO₃, HO₂C(C₀-C₄)alkyl-,R⁶O₂C(C₀-C₄)alkyl-, and R⁶R⁷NCO(C₀-C₄)alkyl-, or  alternatively, R¹ andR², when on adjacent carbon atoms, may be taken together to bemethylenedioxy or ethylenedioxy; R³ is a 5- or 6-membered heterocyclicring system containing up to 4 heteroatoms selected from N, O, and S,said heterocyclic ring system being optionally substituted with 0-3 R⁵,wherein when R⁵ is hydroxy the heterocycle may undergo tautomerizationto an oxo species or may exist as an equilibrium mixture of bothtautomers; R⁴ is selected from F, Cl, Br, I, NO₂, CF₃, CN, C₁-C₄alkoxy-,OH, oxo, CF₃O, haloalkyloxy, C₀-C₄ alkylhydroxy, C₁-C₄ alkyl-,C₁-C₄alkylcarbonyl-, C₀-C₄ alkylOCOR⁶, C₀-C₄ alkylOC(═O)OR⁶, C₀-C₄alkylOC(═O)NR⁶R⁷, NH₂, NHR⁶, C₀-C₄ alkylNR⁶R⁷, C₀-C₄ alkylNR⁷C(═O)OR⁶,C₀-C₄ alkylNR⁶SO₂NR⁶R⁷, C₀-C₄ alkylNR⁷SO₂R⁶, C₀-C₄ alkylSR⁶, C₀-C₄alkylS(O)R⁶, C₀-C₄ alkylSO₂R⁶, SO₃R⁷, C₀-C₄ alkylSO₂NR⁶R⁷, C₀-C₄alkylSO₂NR⁷CO(CR⁹R¹⁰)₀₋₃R⁶, C₀-C₄ alkylCO₂H, C₀-C₄ alkylCO₂R⁶, C₀-C₄alkylCONR⁶R⁷, and C₀-C₄alkylCONR⁷SO₂(CR⁹R¹⁰)₀₋₃R⁶; R⁵ is selected fromthe group consisting of H, C₁-C₄ alkyl, C₃-C₇ cycloalkyl, F, Cl, Br, I,NO₂, CN, CF₃, OCF₃, OH, oxo, C₁-C₄alkoxy-, hydroxyC₁-C₄ alkyl-, C₁-C₄alkylcarbonyl-, CO₂H, CO₂R⁶, CONR⁶R⁷, NHR⁶, and NR⁶R⁷; R⁶ is selectedfrom the group consisting of H, C₁-C₈ alkyl, C₃-C₆ alkenyl, C₃-C₆alkynyl, C₃-C₁₀ cycloalkyl(C₀-C₄ alkyl)-, aryl(C₀-C₄ alkyl)-, andheterocyclic (C₀-C₄ alkyl)-,  wherein said aryl or heterocyclic groupsare substituted with 0-2 substituents independently selected from thegroup consisting of C₁-C₄ alkyl, C₁-C₄ alkoxy, hydroxy C₀-C₄ alkyl, oxo,F, Cl, Br, CF₃, NO₂, CN, OCF₃, NH₂, NHR⁷, NR⁷R⁸, SR⁷, S(O)R⁷, SO₂R⁷,SO₂NR⁷R⁸, CO₂H, CO₂R⁷, and CONR⁷R⁸; R⁷ and R⁸ are each independentlyselected from the group consisting of H, C₁-C₈ alkyl, C₃-C₆ alkenyl,C₃-C₆ alkynyl, C₃-C₁₀ cycloalkyl(C₀-C₄ alkyl)-, C₁-C₆ alkylcarbonyl,C₃-C₇ cycloalkyl(C₀-C₅ alkyl)carbonyl, C₁-C₆ alkoxycarbonyl, C₃-C₇cycloalkyl(C₀-C₅ alkoxy)carbonyl, aryl(C₁-C₅ alkoxy)carbonyl,arylsulfonyl, aryl(C₀-C₄ alkyl)-, heterocyclic(C₁-C₅ alkoxy)carbonyl,heterocyclic sulfonyl and heterocyclic (C₀-C₄ alkyl)-, wherein said arylor heterocyclic groups are substituted with 0-2 substituentsindependently selected from the group consisting of C₁-C₄ alkyl, C₁-C₄alkoxy, F, Cl, Br, CF₃, CN, and NO₂; alternatively, R⁶ and R⁷, or R⁶ andR⁸, or R⁷ and R⁸, when both substituents are on the same nitrogen atom,can be taken together with the nitrogen atom to which they are attachedto form a heterocycle selected from the group consisting of1-aziridinyl, 1-azetidinyl, 1-piperidinyl, 1-morpholinyl,1-pyrrolidinyl, thiamorpholinyl, thiazolidinyl, and 1-piperazinyl, saidheterocycle being optionally substituted with 0-3 groups selected fromthe group consisting of oxo, C₁-C₆ alkyl, C₃-C₇ cycloalkyl(C₀-C₄alkyl)-, C₁-C₆ alkylcarbonyl, C₃-C₇ cycloalkyl(C₀-C₅ alkyl)carbonyl,C₁-C₆ alkoxycarbonyl, C₃-C₇ cycloalkyl(C₀-C₅ alkoxy)carbonyl, aryl(C₀-C₅alkyl), heterocycdic(C₀-C₅ alkyl), aryl(C₁-C₅ alkoxy)carbonyl,heterocyclic(C₁-C₅ alkoxy)carbonyl, C₁-C₆ alkylsulfonyl, arylsulfonyl,and heterocyclicsulfonyl,  wherein said aryl or heterocyclic groups aresubstituted with 0-2 substituents independently selected from the groupconsisting of C₁-C₄ alkyl, C₁-C₄ alkoxy, F, Cl, Br, CF₃, CN, and NO₂; Jis selected from the group consisting of —NR⁷— and —C(═O)—; K isselected from the group consisting of —NR⁷—, —C(═O)—, and —CHR⁹—; L isselected from the group consisting of a single bond, —C(═O), —CR¹⁰R¹¹—,—C(═O)CR¹⁰R¹¹—, —CR¹⁰R¹¹C(═O)—, —CR¹⁰R¹¹C(═O)—, —HR¹⁵C—CHR¹⁶—, and—R¹⁵C═CR¹⁶; R⁹ is selected from the group consisting of H, C₁-C₈ alkyl,C₃-C₆ alkenyl, C₃-C₁₀ cycloalkyl(C₀-C₄ alkyl)-, aryl(C₀-C₄ alkyl)-, andheterocyclic(C₀-C₄ alkyl)-,  wherein said aryl or heterocyclic groupsare substituted with 0-2 substituents independently selected from thegroup consisting of C₁-C₄ alkyl, C₁-C₄ alkoxy, F, Cl, Br, CF₃, and NO₂;R¹⁰ is selected from the group consisting of H, F, Cl, Br, C₁-C₆ alkoxy,C₁-C₈ alkyl, C₃-C₆ alkenyl, C₃-C₁₀ cycloalkyl(C₀-C₄ alkyl)-, aryl(C₀-C₄alkyl)-, and heterocyclic(C₀-C₄ alkyl)-, wherein said aryl orheterocyclic groups are substituted with 0-2 substituents independentlyselected from the group consisting of C₁-C₄ alkyl, C₁-C₄ alkoxy, F, Cl,Br, CF₃, CN, and NO₂; R¹¹ is selected from the group consisting of H, F,Cl, Br, OMe, C₁-C₈ alkyl, C₃-C₆ alkenyl, C₃-C₁₀ cycloalkyl(C₀-C₄alkyl)-, aryl(C₀-C₄ alkyl)-, and heterocyclic(C₀-C₄ alkyl)-, whereinsaid aryl or heterocyclic groups are substituted with 0-2 substituentsindependently selected from the group consisting of C₁-C₄ alkyl, C₁-C₄alkoxy, F, Cl, Br, CF₃, CN, and NO₂; alternatively, R¹⁰ and R¹¹, when onthe same carbon atom, can be taken together with the carbon atoms towhich they are attached to form a 3-7 membered carbocyclic or 3-7membered heterocyclic non-aromatic ring system, said carbocyclic orheterocyclic ring being optionally substituted with 0-2 substituentsindependently selected from the group consisting of C₁-C₄ alkyl, C₁-C₄alkoxy, hydroxy C₀-C₄ alkyl, oxo, F, Cl, Br, CF₃, and NO₂; X is selectedfrom the group consisting of OR¹², NR¹²R¹³, C₁-C₈ alkyl, C₃-C₆ alkenyl,C₃-C₁₀ cycloalkyl(C₀-C₄ alkyl)-, C₆-C₁₀ aryl(C₀-C₄ alkyl)-, andheterocyclic(C₀-C₄ alkyl)-,  wherein said aryl or heterocyclic groupsare substituted with 0-3 substituents independently selected from R¹⁴,with the proviso that when L is a single bond, X cannot be NR¹²R¹³; R¹²is selected from the group consisting of H, C₁-C₈ alkyl, C₃-C₆ alkenyl,C₃-C₁₀ cycloalkyl(C₀-C₄ alkyl)-, monocyclic or bicyclic aryl(C₀-C₄alkyl)-, and monocyclic or bicyclic 5-10 membered heterocyclic(C₀-C₄alkyl)-, and —CZ¹Z²Z³,  wherein said aryl or heterocyclic groups aresubstituted with 0-3 substituents independently selected from R¹⁴; Z¹ isselected from the group consisting of C₁-C₈ alkyl, C₂-C₆ alkenyl, C₂-C₆alkynyl, C₁-C₆ hydroxyalkyl, C₁-C₄ alkoxy C₁-C₄ alkyl, aryl(C₀-C₄alkyl)-, and 4-10 membered heterocyclic (C₀-C₄ alkyl)-,  wherein saidaryl or heterocyclic groups are substituted with 0-3 substituentsindependently selected from R¹⁴; Z² is selected from the groupconsisting of C₁-C₈ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₁-C₆hydroxyalkyl, C₁-C₄ alkoxy C₁-C₄ alkyl, C₁-C₆ NR¹⁷R¹⁸, aryl(C₀-C₄alkyl)-, and 4-10 membered heterocyclic (C₀-C₄ alkyl)-,  wherein saidaryl or heterocyclic groups are substituted with 0-3 substituentsindependently selected from R¹⁴; Z³ is selected from the groupconsisting of C₁-C₈ alkyl, R¹⁴(C₂-C₄ alkyl)-, C₂-C₆ alkenyl, C₂-C₆alkynyl, C₁-C₆ hydroxyalkyl, C₁-C₄ alkoxy C₁-C₄ alkyl, aryl(C₀C₄alkyl)-, 4-10 membered heterocyclic (C₀-C₄ alkyl)-, R¹⁷O═C(C₀-C₄alkyl)-, R¹⁷OO═C(C₀-C₄ alkyl)-, and R¹⁷R¹⁸NO═C(C₀-C₄ alkyl)-,  whereinsaid aryl or heterocyclic groups are substituted with 0-3 substituentsindependently selected from R¹⁴; alternatively, Z¹ and Z², when on thesame carbon atom, can be taken together with the carbon atoms to whichthey are attached to form a 3-7 membered carbocyclic or 3-7 memberedheterocyclic non-aromatic ring system, said carbocyclic or heterocyclicring being optionally substituted with 0-2 substituents independentlyselected from R¹⁴. R¹³ is selected from the group consisting of H, C₁-C₈alkyl, C₃-C₆ alkenyl, C₃-C₁₀ cycloalkyl(C₀-C₄ alkyl)-, C₁-C₆alkylcarbonyl, C₁-C₆ alkylsulfonyl, C₃-C₇ cycloalkyl(C₀-C₅alkyl)carbonyl, C₁-C₆ alkoxycarbonyl, C₃-C₇ cycloalkyl(C₀-C₅alkoxy)carbonyl, aryl(C₀-C₄ alkyl)-, aryl(C₁-C₅ alkoxy)carbonyl ,arylsulfonyl, heterocyclic(C₀-C₄ alkyl), heterocyclic(C₁-C₅alkoxy)carbonyl, and heterocyclicsulfonyl,  wherein said aryl orheterocyclic groups are substituted with 0-2 substituents independentlyselected from the group consisting of C₁-C₄ alkyl, C₁-C₄ alkoxy, F, Cl,Br, CF₃, CN, and NO₂; alternatively, R¹² and R¹³, when both are on thesame nitrogen atom, can be taken together with the nitrogen atom towhich they are attached to form a heterocycle selected from1-aziridinyl, 1-azetidinyl, 1-piperidinyl, 1-morpholinyl,1-pyrrolidinyl, thiamorpholinyl, thiazolidinyl, and 1-piperazinyl,  saidheterocycle being optionally substituted with 0-3 groups independentlyselected from oxo, C₁-C₆ alkyl, C₃-C₇ cycloalkyl(C₀-C₄ alkyl)-, C₁-C₆alkylcarbonyl, C₃-C₇ cycloalkyl(C₀-C₅ alkyl)carbonyl, C₁-C₆alkoxycarbonyl, C₃-C₇ cycloalkyl(C₀-C₅ alkoxy)carbonyl,heterocyclic(C₁-C₅ alkoxy)carbonyl, C₁-C₆ alkylsulfonyl arylsulfonyl andheterocyclicsulfonyl,  wherein said aryl or heterocyclic groups aresubstituted with 0-2 substituents independently selected from the groupconsisting of CH₃—, alkoxy, F, Cl, Br, CF₃, CN, and NO₂; R¹⁴ is selectedfrom the group consisting of H, C₁-C₁₀ alkyl, NO₂, CF₃, CN, F, Cl, Br,C₁-C₁₀ alkylcarbonyl, haloalkyl, haloalkoxy, OH, NR⁶R⁷(C₀-C₄ alkyl)-,R⁶C(═O)O(C₀-C₄ alkyl)-, R⁶OC(═O)O(C₀-C₄ alkyl)-, R⁶O(C₀-C₄ alkyl),R⁶R⁷NC(═O)O(C₀-C₄ alkyl)-, R⁶R⁷NC(═O)(C₀-C₄ alkyl)-,R⁶O(CR¹⁰R¹¹)₂₋₆R⁶NC(═O)(C₀-C₄ alkyl)-, R⁶R⁷N(CR¹⁰R¹¹)₂₋₆R⁶NC(═O)(C₀-C₄alkyl)-, R⁶O₂C(CH₂)₁₋₄O(C₀-C₄ alkyl)-, R⁶OOC(C₁-C₄ alkoxy)-, R⁶OOC(C₀-C₄alkyl)-, R⁶C(═O)(C₀-C₄ alkyl)-, R⁶C(═O)NR⁷(C₀-C₄ alkyl)-,R⁶OC(═O)NR⁷(C₀-C₄ alkyl)-, R⁶OC(═NCN)NR⁷(C₀-C₄ alkyl)-,R⁶R⁷NC(═O)NR⁸(C₀-C₄ alkyl)-, R⁶OC(═NC)NR⁷(C₀-C₄ alkyl)-, R⁶(CR¹⁰R¹¹)₁₋₄NR⁷C═O—, R⁶O(CR¹⁰R¹¹)₁₋₄O═CR⁷N—, NR⁶R⁷(CR¹⁰R¹¹)₁₋₄ C═O R⁷N—,R⁶O(CR¹⁰R¹¹)₂₋₄R⁷N—, R⁶O₂C(CR¹⁰R¹¹)₁₋₄R⁷N, R⁶R⁷N(CR¹⁰R¹¹)₂₋₄R⁷N—,R⁶R⁷NC(═NCN)NR⁷(C₀-C₄ alkyl)-, R⁶R⁷NC(═C(H)(NO₂))NR⁷(C₀-C₄ alkyl)-,R⁷R⁸NC(═NR⁷)NR⁷(C₀-C₄ alkyl)-, R⁶R⁷N SO₂NR⁸(C₀-C₄ alkyl)-,R⁶SO₂NR⁷(C₀-C₄ alkyl)-, R⁶R⁷N(C₁-C₄)CO—, R⁶R⁷N(C₂-C₆ alkyl)O—,R⁶CO(CR¹⁰R¹¹)₀₋₂ R⁷N(O₂)S(C₀-C₄ alkyl), R⁶(O₂)S R⁷NC(═O)(C₀-C₄ alkyl)-,R⁶S(C₀-C₄ alkyl)-, R⁶S(═O)(C₀-C₄ alkyl)-, R⁶SO₂(C₀-C₄ alkyl)-, SO₂NR⁶R⁷,SiMe₃, R⁶R⁷N(C₂-C₄ alkyl)-, R⁶R⁷N(C₂-C₄ alkoxy)-, HSO₃, HONH—, R⁶ONH—,R⁸R⁷NNR⁶—, HO(COR⁶)N—, HO(R⁶O₂C)N, C₂-C₆ alkenyl, C₃-C₁₀ cycloalkyl,C₃-C₁₀ cycloalkylmethyl, aryl(C₀-C₄alkyl)-, heteroaryl(C₀-C₄alkyl)-,aryl(C₀-C₄alkyl)O—, and heteroaryl(C₀-C₄alkyl)O—,  wherein said arylgroups are substituted with 0-2 substituents independently selected froma group consisting of C₁-C₄ alkyl, C₁-C₄ alkoxy, F, Cl, Br, CF₃, andNO₂; R¹⁵ is selected from the group consisting of H, halo, cyano, C₁-C₈alkyl, C₃-C₆ alkenyl, and C₃-C₁₀ cycloalkyl(C₀-C₄ alkyl)-, aryl(C₀-C₄alkyl)-, and heterocyclic(C₀-C₄ alkyl)-,  wherein said aryl orheterocyclic groups are substituted with 0-2 substituents independentlyselected from R¹⁴; and R¹⁶ is selected from the group consisting of H,halo, cyano, C₁-C₈ alkyl, C₃-C₆ alkenyl, C₃-C₁₀ cycloalkyl(C₀-C₄alkyl)-, aryl(C₀-C₄ alkyl)-, and heterocyclic(C₀-C₄ alkyl)-,  whereinsaid aryl or heterocyclic groups are substituted with 0-2 substituentsindependently selected from R¹⁴; alternatively, when R¹⁵ and R¹⁶ are onadjacent carbon atoms, or when R¹⁵ and R¹⁶ are oriented on the same sideof the double bond, as depicted in the following structure (III)

 R¹⁵ and R¹⁶ can be taken together with the carbon atoms to which theyare attached to form a 3-7 membered carbocyclic aromatic or nonaromaticring system, or a 3-7 membered heterocyclic aromatic or nonaromatic ringsystem, said carbocyclic or heterocyclic ring being optionallysubstituted with 0-2 substituents independently selected from the groupconsisting of C₁-C₄ alkyl, C₁-C₄ alkoxy, F, Cl, Br, CF₃, NO₂; R¹⁷ isselected from the group consisting of H, C₁-C₈ alkyl, C₃-C₆ alkenyl,C₃-C₁₀ cycloalkyl(C₀-C₄ alkyl)-, C₁-C₆ alkylcarbonyl, C₁-C₆alkylsulfonyl, C₃-C₇ cycloalkyl(C₀-C₅ alkyl)carbonyl, C₁-C₆alkoxycarbonyl, C₃-C₇ cycloalkyl(C₀-C₅ alkoxy)carbonyl,hydroxy(C₂-C₄)alkyl-, C₁-C₃ alkoxy(C₂-C₄)alkyl-, (C₀-C₄ alkyl)(C₀-C₄alkyl) amino(C₂-C₄)alkyl-, aryl(C₀-C₄ alkyl)-, aryl(C₁-C₅alkoxy)carbonyl, arylsulfonyl, heterocyclic(C₀-C₄ alkyl),heterocyclic(C₁-C₅ alkoxy)carbonyl, and heterocyclicsulfonyl,  whereinsaid aryl or heterocyclic groups are substituted with 0-2 substituentsindependently selected from the group consisting of C₁-C₄ alkyl, C₁-C₄alkoxy, C₁-C₄ alkoxy C₁-C₄ alkyl, oxo, F, Cl, Br, CF₃, CN, and NO₂; R¹⁸is selected from the group consisting of H, C₁-C₈ alkyl, C₃-C₆ alkenyl,C₃-C₁₀ cycloalkyl(C₀-C₄ alkyl)-, aryl(C₀-C₄ alkyl)-, andheterocyclic(C₀-C₄ alkyl),  wherein said aryl or heterocyclic groups aresubstituted with 0-2 substituents independently selected from the groupconsisting of C₁-C₄ alkyl, C₁-C₄ alkoxy, F, Cl, Br, CF₃, CN, and NO₂;and alternatively, R¹⁷ and R¹⁸, when both are on the same nitrogen atom,can be taken together with the nitrogen atom to which they are attachedto form a heterocycle selected from 1-aziridinyl, 1-azetidinyl,1-piperidinyl, 1-morpholinyl, 1-pyrrolidinyl, thiamorpholinyl,thiazolidinyl, and 1-piperazinyl,  said heterocycle being optionallysubstituted with 0-3 groups selected from oxo, C₁-C₆ alkyl, C₃-C₇cycloalkyl(C₀-C₄ alkyl)-, C₁-C₆ alkylcarbonyl, (C₁-C₆alkylcarbonyl)(C₀-C₄alkyl)amino-, C₃-C₇ cycloalkyl(C₀-C₅ alkyl)carbonyl,C₁-C₆ alkoxycarbonyl, C₃-C₇ cycloalkyl(C₀-C₅ alkoxy)carbonyl, aryl(C₀-C₅alkyl), heterocyclic(C₀-C₅ alkyl), aryl(C₁-C₅ alkoxy)carbonyl,heterocyclic(C₁-C₅ alkoxy)carbonyl, C₁-C₆ alkylsulfonyl arylsulfonyl andheterocyclicsulfonyl,  wherein said aryl or heterocyclic groups aresubstituted with 0-2 substituents independently selected from the groupconsisting of CH₃—, alkoxy, F, Cl, Br, CF₃, CN, and NO₂.
 2. A compoundof claim 1, or a pharmaceutically acceptable salt thereof, wherein: Z iseither a 5, 6 or 7 membered monocyclic ring system substituted with R³or R⁴ and optionally substituted with 0-4 substituents chosen from R¹ orR², or a 9 or 10 membered bicyclic ring system optionally substitutedwith 0-5 substituents chosen from R¹, R², R³ or R⁴, said ring systemsoptionally contain up to 4 heteroatoms selected from N, O, and S, andwherein a CH₂ adjacent to any of the said N, O or S heteroatoms isoptionally substituted with oxo (═O); R³ is a 5- or 6-memberedheterocyclic ring system containing up to 4 heteroatoms selected from N,O, and S, said heterocyclic ring system being optionally substitutedwith 0-1 R⁵, wherein when R⁵ is hydroxy the heterocycle may undergotautomerization to an oxo species or may exist as an equilibrium mixtureof both tautomers; J and K are taken together to be selected from:—NHC(═O)—, —NHCHR⁹—, and —C(═O)NH—; X is selected from the groupconsisting of OR¹², NR¹²R¹³, C₃-C₁₀ cycloalkyl(C₀-C₄ alkyl)-, C₆-C₁₀aryl(C₀-C₄ alkyl)-, and heterocyclic(C₀-C₄ alkyl)-,  wherein said arylor heterocyclic groups are substituted with 0-3 substituentsindependently selected from R¹⁴, with the proviso that when L is asingle bond, X cannot be NR¹²R¹³; and R¹² is selected from the groupconsisting of ethyl, C₃-C₁₀ cycloalkyl(C₀-C₄ alkyl)-, monocyclic orbicyclic aryl(C₀-C₄ alkyl)-, and monocyclic or bicyclic 5-10 memberedheterocyclic(C₀-C₄ alkyl)-, and —CZ¹Z²Z³,  wherein said aryl orheterocyclic groups are substituted with 0-3 substituents independentlyselected from R¹⁴.
 3. A compound of claim 1, or a pharmaceuticallyacceptable salt thereof, said compound selected from the groupconsisting of:N-(4-Fluorophenyl)-N2-[3-methoxy-4-(5-oxazolyl)phenyl]glycinamide;N-[3-Methoxy-4-(5-oxazolyl)phenyl]-N2-phenylglycinamide;N-[3-Methoxy-4-(5-oxazolyl)phenyl]-N2-(3-methylphenyl)glycinamide;[[3-Methoxy-4-(5-oxazolyl)phenyl]amino]oxoacetic acid ethyl ester;N-[3-Methoxy-4-(5-oxazolyl)phenyl]-N′-phenylethanediamide;N-[3-Methoxy-4-(5-oxazolyl)phenyl]-N′-(2-methylphenyl)ethanediamide;N-[3-Methoxy-4-(5-oxazolyl)phenyl]-N′-(3-methylphenyl)ethanediamide;N-[3-Methoxy-4-(5-oxazolyl)phenyl]-N′-(4-methylphenyl)ethanediamide;(S)-[[3-[[[[3-Methoxy-4-(5-oxazolyl)phenyl]amino]oxoacetyl]amino]phenyl]methyl]carbamicacid tetrahydro-3-furanyl ester;N-[3-Methoxy-4-(5-oxazolyl)phenyl]-N′-(3-methoxyphenyl)ethanediamide;N-[3-Methoxy-4-(5-oxazolyl)phenyl]-N′-(phenylmethyl)ethanediamide;N-(4-Cyanophenyl)-N′-[3-methoxy-4-(5-oxazolyl)phenyl]ethanediamide;3-[[3-Methoxy-4-(5-oxazolyl)phenyl]amino]-3-oxopropanoic acid ethylester;N-[3-Methoxy-4-(5-oxazolyl)phenyl]-N′-(3-methylphenyl)propanediamide;N-[3-Methoxy-4-(5-oxazolyl)phenyl]-N′-(phenyl)propanediamide;(S)-[[3-[[3-[[3-Methoxy-4-(5-oxazolyl)phenyl]amino]-1,3-dioxopropyl]amino]phenyl]methyl]carbamicacid tetrahydro-3-furanyl ester;N-[3-Methoxy-4-(5-oxazolyl)phenyl]benzeneacetamide;N-[3-Methoxy-4-(5-oxazolyl)phenyl]-α-oxobenzeneacetamide;N-[3-Methoxy-4-(5-oxazolyl)phenyl]-1H-indole-2-carboxamide;N-(1,1-Dimethylethyl)-N′-[3-methoxy-4-(5-oxazolyl)phenyl]ethanediamide;N-[1,1-Bis(hydroxymethyl)propyl]-N′-[3-methoxy-4-(5-oxazolyl)phenyl]ethanediamide;N-(2-Hydroxy-1,1-dimethylethyl)-N′-[3-methoxy-4-(5-oxazolyl)phenyl]ethanediamide;N-[[[3-Methoxy-4-(5-oxazolyl)phenyl]amino]oxoacetyl]-2-methylalanine1,1-dimethylethyl ester;N-(2-Hydroxy-1,1-dimethylpentyl)-N′-[3-methoxy-4-(5-oxazolyl)phenyl]ethanediamide;N-[2-[(2-Hydroxy-1,1-dimethylethyl)amino]-1,1-dimethylethyl]-N′-[3-methoxy-4-(5-oxazolyl)phenyl]ethanediamide;N-[2-(Dimethylamino)-1,1-dimethylethyl]-N′-[3-methoxy-4-(5-oxazolyl)phenyl]ethanediamide;N-(1,1-Diethyl-2-propynyl)-N′-[3-methoxy-4-(5-oxazolyl)phenyl]ethanediamide;N-[3-Methoxy-4-(5-oxazolyl)phenyl]-N′-(1,1,3,3-tetramethylbutyl)ethanediamide;N-(1,1-Dimethylpropyl)-N′-[3-methoxy-4-(5-oxazolyl)phenyl]ethanediamide;N-[1-(Hydroxymethyl)cyclopentyl]-N′-[3-methoxy-4-(5-oxazolyl)phenyl]ethanediamide;N-[2-(4-Fluorophenyl)-1,1-dimethylethyl]-N′-[3-methoxy-4-(5-oxazolyl)phenyl]ethanediamide;N-[[[3-Methoxy-4-(5-oxazolyl)phenyl]amino]oxoacetyl]-α-methyltyrosinemethyl ester;N-[[[3-Methoxy-4-(5-oxazolyl)phenyl]amino]oxoacetyl]-α-methyltryptophanmethyl ester;N-[1,1-Bis(hydroxymethyl)ethyl]-N′-[3-methoxy-4-(5-oxazolyl)phenyl]-N-methylethanediamide;N-(1,1-Dimethyl-3-oxobutyl)-N′-[3-methoxy-4-(5-oxazolyl)phenyl]ethanediamide;N-[3-Methoxy-4-(5-oxazolyl)phenyl]-N′-(1-methyl-1-phenylethyl)ethanediamide;N-[[[3-Methoxy-4-(5-oxazolyl)phenyl]amino]oxoacetyl]-2-methylalaninemethyl ester;1-[[[[3-Methoxy-4-(5-oxazolyl)phenyl]amino]oxoacetyl]amino]cyclopropanecarboxylicacid methyl ester;N-(1-Ethynylcyclohexyl)-N′-[3-methoxy-4-(5-oxazolyl)phenyl]ethanediamide;and(R)-N-[1-(Hydroxymethyl)-1-methylpropyl]-N′-[3-methoxy-4-(5-oxazolyl)phenyl]-N-methylethanediamide;(E)-N-[3-Methoxy-4-(5-oxazolyl)phenyl]-3-phenyl-2-propenamide;N-[3-Methoxy-4-(5-oxazolyl)phenyl]benzamide;N-[3-Methoxy-4-(5-oxazolyl)phenyl-1-methyl-1H-indole-2-carboxamide;N-[3-Methoxy-4-(5-oxazolyl)phenyl]-2-benzofurancarboxamide;N-[3-Methoxy-4-(5-oxazolyl)phenyl]benzo[b]thiophene-2-carboxamide;N-[3-Methoxy-4-(5-oxazolyl)phenyl]-1,3-benzodioxole-5-carboxamide;7-Methoxy-N-[3-methoxy-4-(5-oxazolyl)phenyl]-2-benzofurancarboxamide;5-Hydroxy-N-[3-methoxy-4-(5-oxazolyl)phenyl]-1H-indole-2-carboxamide;N-[3-Methoxy-4-(5-oxazolyl)phenyl]-5-(2-pyridinyl)-2-thiophenecarboxamide;5-(1,1-Dimethylethyl)-N-[3-methoxy-4-(5-oxazolyl)phenyl]-2-furancarboxamide;N-[3-Methoxy-4-(5-oxazolyl)phenyl]-5-methyl-2-thiophenecarboxamide;N-[3-Methoxy-4-(5-oxazolyl)phenyl]-1-methyl-1H-pyrrole-2-carboxamide;N-[3-Methoxy-4-(5-oxazolyl)phenyl]-4,5-dimethyl-2-furancarboxamide;(E)-N-[3-Methoxy-4-(5-oxazolyl)phenyl]-3-(4-methylphenyl)-2-propenamide;(E)-N-[3-Methoxy-4-(5-oxazolyl)phenyl]-3-(4-methylphenyl)-2-propenamide;(E)-3-(2-Fluorophenyl)-N-[3-methoxy-4-(5-oxazolyl)phenyl]-2-propenamide;(E)-3-(3-Fluorophenyl)-N-[3-methoxy-4-(5-oxazolyl)phenyl]-2-propenamide;(E)-3-(4-Fluorophenyl)-N-[3-methoxy-4-(5-oxazolyl)phenyl]-2-propenamide;(E)-3-(2-Chlorophenyl)-N-[3-methoxy-4-(5-oxazolyl)phenyl]-2-propenamide;(E)-3-(3-Chlorophenyl)-N-[3-methoxy-4-(5-oxazolyl)phenyl]-2-propenamide;(E)-3-(3-Chlorophenyl)-N-[3-methoxy-4-(5-oxazolyl)phenyl]-2-propenamide;(E)-N-[3-Methoxy-4-(5-oxazolyl)phenyl]-3-[2-(trifluoromethyl)phenyl]-2-propenamide;(E)-3-(3-Cyanophenyl)-N-[3-methoxy-4-(5-oxazolyl)phenyl]-2-propenamide;(E)-3-[4-(Acetylamino)phenyl]-N-[3-methoxy-4-(5-oxazolyl)phenyl]-2-propenamide;(E)-3-(2,3-Dimethoxyphenyl)-N-[3-methoxy-4-(5-oxazolyl)phenyl]-2-propenamide;(E)-3-(2,6-Difluorophenyl)-N-[3-methoxy-4-(5-oxazolyl)phenyl]-2-propenamide;(E)-N-[3-Methoxy-4-(5-oxazolyl)phenyl]-3-(2,3,4-trimethoxyphenyl)-2-propenamide;(E)-2-Fluoro-N-[3-methoxy-4-(5-oxazolyl)phenyl]-3-phenyl-2-propenamide;(E)-3-(2-Furanyl)-N-[3-methoxy-4-(5-oxazolyl)phenyl]-2-propenamide;(E)-N-[3-Methoxy-4-(5-oxazolyl)phenyl]-3-(2-thienyl)-2-propenamide;(E)-N-[3-Methoxy-4-(5-oxazolyl)phenyl]-3-(3-pyridinyl)-2-propenamide;(E)-N-[3-Methoxy-4-(5-oxazolyl)phenyl]-3-(4-pyridinyl)-2-propenamide;(E)-N-[3-Methoxy-4-(5-oxazolyl)phenyl]-3-(1-naphthalenyl)-2-propenamide;N-[3-Methoxy-4-(5-oxazolyl)phenyl]-3,4-dimethylbenzamide;N-[3-Methoxy-4-(5-oxazolyl)phenyl]-2-indolizinecarboxamide;(E)-N-[3-Methoxy-4-(5-oxazolyl)phenyl]-3-[3-methoxy-4-(phenylmethoxy)phenyl]-2-propenamide;5-Hydroxy-N-[3-methoxy-4-(5-oxazolyl)phenyl]-1H-indole-2-carboxamide;N-[3-Methoxy-4-(5-oxazolyl)phenyl]-2,4-dimethyl-5-thiazolecarboxamide;and 8-Hydroxy-N-[3-methoxy-4-(5-oxazolyl)phenyl]-2-quinolinecarboxamide4. A pharmaceutical composition for the treatment of an IMPDH-associateddisorder, comprising a pharmaceutically acceptable carrier, adjuvant orvehicle and at least one compound of claim 1, or a pharmaceuticallyacceptable salt thereof, in an amount effective therefor.
 5. Apharmaceutical composition for the treatment of an IMPDH-associateddisorder, comprising a pharmaceutically acceptable carrier, adjuvant orvehicle and at least one compound of claim 2, or a pharmaceuticallyacceptable salt thereof, in an amount effective therefor.
 6. Apharmaceutical composition for the treatment of an IMPDH-associateddisorder, comprising a pharmaceutically acceptable carrier, adjuvant orvehicle and at least one compound of claim 3, or a pharmaceuticallyacceptable salt thereof, in an amount effective therefor.
 7. A methodfor the treatment of an IMPDH-associated disorder, comprising the stepof administering to a subject in need thereof an amount effectivetherefor of at least one compound of claim 1 or a pharmaceuticallyacceptable salt thereof.
 8. A method for the treatment of anIMPDH-associated disorder, comprising the step of administering to asubject in need thereof an amount effective therefor of at least onecompound of claim 2 or a pharmaceutically acceptable salt thereof.
 9. Amethod for the treatment of an IMPDH-associated disorder, comprising thestep of administering to a subject in need thereof an amount effectivetherefor of at least one compound of claim 3 or a pharmaceuticallyacceptable salt thereof.
 10. The method of claim 7, wherein saidIMPDH-associated disorder is selected from the group consisting of anautoimmune disorder, an inflamatory disorder, a cancer or tumordisorder, a DNA or RNA viral replication disease, and allograftrejection.
 11. The method of claim 8, wherein said IMPDH-associateddisorder is selected from the group consisting of an autoimmunedisorder, an inflamatory disorder, a cancer or tumor disorder, a DNA orRNA viral replication disease, and allograft rejection.
 12. The methodof claim 9, wherein said IMPDH-associated disorder is selected from thegroup consisting of an autoimmune disorder, an inflamatory disorder, acancer or tumor disorder, a DNA or RNA viral replication disease, andallograft rejection.
 13. The method of claim 10, wherein saidIMPDH-associated disorder is selected from transplant rejection,rheumatoid arthritis, inflammatory bowel disease, hepatitis B, hepatitisC, herpes simplex type I, and herpes simplex type II.
 14. The method ofclaim 11, wherein said IMPDH-associated disorder is selected fromtransplant rejection, rheumatoid arthritis, inflammatory bowel disease,hepatitis B, hepatitis C, herpes simplex type I, and herpes simplex typeII.
 15. The method of claim 12, wherein said IMPDH-associated disorderis selected from transplant rejection, rheumatoid arthritis,inflammatory bowel disease, hepatitis B, hepatitis C, herpes simplextype I, and herpes simplex type II.
 16. The method of claim 7, whereinsaid compound of claim 1, or a pharmaceutically acceptable salt thereof,is administered with one or more of: an immunosuppressant, ananti-cancer agent, an anti-viral agent, an anti-inflammatory agent, ananti-fungal agent, an antibiotic, an anti-vascular hyperproliferationcompound, or an IMPDH inhibitor other than a compound of claim 1 or apharmaceutically acceptable salt thereof.
 17. The method of claim 8,wherein said compound of claim 2, or a pharmaceutically acceptable saltthereof, is administered with one or more of: an immunosuppressant, ananti-cancer agent, an anti-viral agent, an anti-inflammatory agent, ananti-fungal agent, an antibiotic, an anti-vascular hyperproliferationcompound, or an IMPDH inhibitor other than a compound of claim 2 or apharmaceutically acceptable salt thereof.
 18. The method of claim 9,wherein said compound of claim 3, or a pharmaceutically acceptable saltthereof, is administered with one or more of: an immunosuppressant, ananti-cancer agent, an anti-viral agent, an anti-inflammatory agent, ananti-fungal agent, an antibiotic, an anti-vascular hyperproliferationcompound, or an IMPDH inhibitor other than a compound of claim 3 or apharmaceutically acceptable salt thereof.
 19. The method of claim 17,wherein said compound of claim 2, or a pharmaceutically acceptable saltthereof, is administered with one or more of: another IMP H inhibitor; acyclosporin; CTLA4-Ig; an antibody selected from anti-ICAM-3, anti-IL-2receptor (Anti-Tac), anti-CD45RB, anti-CD2, anti-CD3 (OKT-3), anti-CD4,anti-CD80, anti-CD86, and monoclonal antibody OKT3; an agent blockingthe interaction between CD40 and CD154; a fusion protein constructedfrom CD40 and/or CD154/gp39; an inhibitor of NF-kappa B function; anon-steroidal antiinflammatory drug (NSAID); a gold compound; anantiviral agent; an antiproliferative ; a cytotoxic drug; an TNF-αinhibitor; an anti-TNF antibody; a soluble TNF receptor; and rapamycin(sirolimus or Rapamune); or derivatives thereof.
 20. A compound of thefollowing Formula I, or a pharmaceutically acceptable salt thereof:

wherein: (1) Z is a saturated, partially saturated or unsaturatedmonocyclic or bicyclic ring system optionally containing up to 4heteroatoms selected from N, O, and S, and wherein a CH₂ adjacent to anyof the said N, O or S heteroatoms is optionally substituted with oxo(═O), and wherein Z is optionally substituted with 0-3 substituentschosen from R¹, R², R³ or R⁴; (2) R¹ and R² are independently selectedfrom the group consisting of H, F, Cl, Br, I, NO₂, CF₃, CN, OCF₃, OH,C₁-C₄alkoxy-, C₁-C₄alkylcarbonyl-, C₁-C₆ alkyl, hydroxy C₁-C₄ alkyl-,C₃-C₆ alkenyl, C₃-C₆ alkynyl, C₃-C₁₀ cycloalkyl(C₀-C₄alkyl)-,H₂N(C₀-C₄)alkyl-, R⁶HN(C₀-C₄)alkyl-, R⁶R⁷N(C₀-C₄)alkyl-,R⁷S(C₀-C₄)alkyl-, R⁷S(O)(C₀-C₄)alkyl-, R⁷SO₂(C₀-C₄)alkyl-,R⁶NSO₂(C₀-C₄)alkyl-; HSO₃, HO₂C(C₀-C₄)alkyl-, R⁶O₂C(C₀-C₄)alkyl-, andR⁶R⁷NCO(C₀-C₄)alkyl-;  alternatively, R¹ and R², when on adjacent carbonatoms, may be taken together to be methylenedioxy or ethylenedioxy; (3)R³ is a 5- or 6-membered heterocyclic ring system containing up to 4heteroatoms selected from N, O, and S, said heterocyclic ring systembeing optionally substituted with 0-3 R⁵, when R⁵ is hydroxy theheterocycle may undergo tautomerization to an oxo species, or exist asan equilibrium mixture of both tautomers; (4) R⁴ is selected from thegroup consisting of H, F, Cl, Br, I, NO₂, CF₃, CN, OCF₃, OH,C₁-C₄alkoxy-, hydroxyC₁-C₄ alkyl-, C₁-C₄ alkylcarbonyl-, NH₂, NHR⁶,NR⁶R⁷, SR⁶, S(O)R⁶, SO₂R⁶, SO₂NR⁶R⁷, CO₂H, CO₂R⁶, and CONR⁶R⁷; (5) R⁵ isselected from the group consisting of H, F, Cl, Br, I, NO₂, CN, CF₃,OCF₃, OH, oxo, C₁-C₄alkoxy-, hydroxyC₁-C₄ alkyl-, C₁-C₄ alkylcarbonyl-,CO₂H, CO₂R⁶, CONR⁶R⁷, NHR⁶, and NR⁶R⁷; (6) R⁶ is selected from the groupconsisting of H, C₁-C₈ alkyl, C₃-C₆ alkenyl, C₃-C₆ alkynyl, C₃-C₁₀cycloalkyl(C₀-C₄ alkyl)-, aryl(C₀-C₄ alkyl)-, and heterocyclic (C₀-C₄alkyl)-,  wherein said aryl or heterocyclic groups are substituted with0-2 substituents independently selected from the group consisting ofC₁-C₄ alkyl, C₁-C₄ alkoxy, hydroxy C₀-C₄ alkyl, oxo, F, Cl, Br, CF₃,NO₂, CN, OCF₃, NH₂, NHR⁷, NR⁷R⁸, SR⁷, S(O)R⁷, SO₂R⁷, SO₂NR⁷R⁸, CO₂H,CO₂R⁷, and CONR⁷R⁸; (7) R⁷ and R⁸ are independently selected from thegroup consisting of H, C₁-C₈ alkyl, C₃-C₆ alkenyl, C₃-C₆ alkynyl, C₃-C₁₀cycloalkyl(C₀-C₄ alkyl)-, C₁-C₆ alkylcarbonyl, C₃-C₇ cycloalkyl(C₀-C₅alkyl)carbonyl, C₁-C₆ alkoxycarbonyl, C₃-C₇ cycloalkyl(C₀-C₅alkoxy)carbonyl, aryl(C₁-C₅ alkoxy)carbonyl, arylsulfonyl, aryl(C₀-C₄alkyl)-, heterocyclic(C₁-C₅ alkoxy)carbonyl, heterocyclic sulfonyl andheterocyclic (C₀-C₄ alkyl)-,  wherein said aryl or heterocyclic groupsare substituted with 0-2 substituents independently selected from thegroup consisting of C₁-C₄ alkyl, C₁-C₄ alkoxy, F, Cl, Br, CF₃, CN, andNO₂; (8) alternatively, R⁶ and R⁷, or R⁶ and R⁸, or R⁷ and R⁸, when bothsubstituents are on the same nitrogen atom [as in (—NR⁶R⁷) or (—NR⁷R⁸)],can be taken together with the nitrogen atom to which they are attachedto form a heterocycle selected from the group consisting of1-aziridinyl, 1-azetidinyl, 1-piperidinyl, 1-morpholinyl,1-pyrrolidinyl, thiamorpholinyl, thiazolidinyl, and 1-piperazinyl, saidheterocycle being optionally substituted with 0-3 groups selected fromthe group consisting of oxo, C₁-C₆ alkyl, C₃-C₇ cycloalkyl(C₀-C₄alkyl)-, C₁-C₆ alkylcarbonyl, C₃-C₇ cycloalkyl(C₀-C₅ alkyl)carbonyl,C₁-C₆ alkoxycarbonyl, C₃-C₇ cycloalkyl(C₀-C₅ alkoxy)carbonyl, aryl(C₀-C₅alkyl), heterocyclic(C₀-C₅ alkyl), aryl(C₁-C₅ alkoxy)carbonyl,heterocyclic(C₁-C₅ alkoxy)carbonyl, C₁-C₆ alkylsulfonyl, arylsulfonyl,and heterocyclicsulfonyl,  wherein said aryl or heterocyclic groups aresubstituted with 0-2 substituents independently selected from the groupconsisting of C₁-C₄ alkyl, C₁-C₄ alkoxy, F, Cl, Br, CF₃, CN, and NO₂;(9) J is selected from the group consisting of —NR⁷—, and —C(═O)—; (10)K is selected from the group consisting of —NR⁷—, —C(═O)—, and —CHR⁹—;(11) L is selected from the group consisting of a single bond (i.e., Lis absent), —C(═O), —CHR⁹—, —C(═O)CHR¹⁰—, —CHR¹⁰C(═O)—, —CR¹⁰R¹¹C(═O)—,—HR¹⁵C—CHR¹⁶—, and —R¹⁵C═CR¹⁶—; (12) R⁹ is selected from the groupconsisting of H, C₁-C₈ alkyl, C₃-C₆ alkenyl, C₃-C₁₀ cycloalkyl(C₀-C₄alkyl)-, aryl(C₀-C₄ alkyl)-, and heterocyclic(C₀-C₄ alkyl)-,  whereinsaid aryl or heterocyclic groups are substituted with 0-2 substituentsindependently selected from the group consisting of C₁-C₄ alkyl, C₁-C₄alkoxy, F, Cl, Br, CF₃, and NO₂; (13) R¹⁰ is selected from the groupconsisting of H, F, Cl, Br, C₁-C₆ alkoxy, C₁-C₈ alkyl, C₃-C₆ alkenyl,C₃-C₁₀ cycloalkyl(C₀-C₄ alkyl)-, aryl(C₀-C₄ alkyl)-, andheterocyclic(C₀-C₄ alkyl)-, wherein said aryl or heterocyclic groups aresubstituted with 0-2 substituents independently selected from the groupconsisting of C₁-C₄ alkyl, C₁-C₄ alkoxy, F, Cl, Br, CF₃, CN, and NO₂;(14) R¹¹ is selected from the group consisting of H, F, Cl, Br, OMe,C₁-C₈ alkyl, C₃-C₆ alkenyl, C₃-C₁₀ cycloalkyl(C₀-C₄ alkyl)-, aryl(C₀-C₄alkyl)-, and heterocyclic(C₀-C₄ alkyl)-, wherein said aryl orheterocyclic groups are substituted with 0-2 substituents independentlyselected from the group consisting of C₁-C₄ alkyl, C₁-C₄ alkoxy, F, Cl,Br, CF₃, CN, and NO₂; (15) alternatively, R¹⁰ and R¹¹, when on the samecarbon atom [as in (—CR¹⁰R¹¹—)], can be taken together with the carbonatoms to which they are attached to form a 3-7 membered carbocyclic or3-7 membered heterocyclic non-aromatic ring system, said carbocyclic orheterocyclic ring being optionally substituted with 0-2 substituentsindependently selected from the group consisting of C₁-C₄ alkyl, C₁-C₄alkoxy, hydroxy C₀-C₄ alkyl, oxo, F, Cl, Br, CF₃, NO₂; (16) X isselected from the group consisting of OR¹², NR¹²R¹³, C₁-C₈ alkyl, C₃-C₆alkenyl, C₃-C₁₀ cycloalkyl(C₀-C₄ alkyl)-, C₆-C₁₀ aryl(C₀-C₄ alkyl)-,—CR⁴═CR⁵(heteroaryl), —CR⁴═CR⁵(aryl), and heterocyclic(C₀-C₄ alkyl)-, wherein said aryl or heterocyclic groups are substituted with 0-3substituents independently selected from R¹⁴, with the proviso that whenL is a single bond (i.e., L is absent), X cannot be NR¹²R¹³; (17) R¹² isselected from the group consisting of H, C₁-C₈ alkyl, C₃-C₆ alkenyl,C₃-C₁₀ cycloalkyl(C₀-C₄ alkyl)-, aryl(C₀-C₄ alkyl)-, and 4-10 memberedheterocyclic(C₀-C₄ alkyl)-,  wherein said aryl or heterocyclic groupsare substituted with 0-3 substituents independently selected from R¹⁴;(18) R¹³ is selected from the group consisting of H, C₁-C₈ alkyl, C₃-C₆alkenyl, C₃-C₁₀ cycloalkyl(C₀-C₄ alkyl)-, C₁-C₆ alkylcarbonyl, C₁-C₆alkylsulfonyl, C₃-C₇ cycloalkyl(C₀-C₅ alkyl)carbonyl, C₁-C₆alkoxycarbonyl, C₃-C₇ cycloalkyl(C₀-C₅ alkoxy)carbonyl, aryl(C₀-C₄alkyl)-, aryl(C₁-C₅ alkoxy)carbonyl, arylsulfonyl, heterocyclic(C₀-C₄alkyl), heterocyclic(C₁-C₅ alkoxy)carbonyl, and heterocyclicsulfonyl, wherein said aryl or heterocyclic groups are substituted with 0-2substituents independently selected from the group consisting of C₁-C₄alkyl, C₁-C₄ alkoxy, F, Cl, Br, CF₃, CN, and NO₂; (19) alternatively,R¹² and R¹³, when both are on the same nitrogen atom [as in (—NR¹²R¹³)]can be taken together with the nitrogen atom to which they are attachedto form a heterocycle selected from 1-aziridinyl, 1-azetidinyl,1-piperidinyl, 1-morpholinyl, 1-pyrrolidinyl, thiamorpholinyl,thiazolidinyl, and 1-piperazinyl,  said heterocycle being optionallysubstituted with 0-3 groups selected from oxo, C₁-C₆ alkyl, C₃-C₇cycloalkyl(C₀-C₄ alkyl)-, C₁-C₆ alkylcarbonyl, C₃-C₇ cycloalkyl(C₀-C₅alkyl)carbonyl, C₁-C₆ alkoxycarbonyl, C₃-C₇ cycloalkyl(C₀-C₅alkoxy)carbonyl, aryl(C₀-C₅ alkyl), heterocyclic(C₀-C₅ alkyl),aryl(C₁-C₅ alkoxy)carbonyl, heterocyclic(C₁-C₅ alkoxy)carbonyl, C₁-C₆alkylsulfonyl arylsulfonyl and heterocyclicsulfonyl,  wherein said arylor heterocyclic groups are substituted with 0-2 substituentsindependently selected from the group consisting of CH₃—, alkoxy, F, Cl,Br, CF₃, CN, and NO₂; (20) R¹⁴ is selected from the group consisting ofH, C₁-C₁₀ alkyl, NO₂, CF₃, CN, F, Cl, Br, C₁-C₁₀ alkylcarbonyl,NR⁶R⁷(C₀-C₄ alkyl)-, R⁶C(═O)O(C₀-C₄ alkyl)-, R⁶OC(═O)O(C₀-C₄ alkyl)-,R⁶O(C₀-C₄ alkyl), R⁶R⁷NC(═O)O(C₀-C₄ alkyl)-, R⁶O₂CCH₂O(C₀-C₄ alkyl)-,R⁶OOC(C₁-C₄ alkoxy)-, R⁶OOC(C₀-C₄ alkyl)-, R⁶C(═O)(C₀-C₄ alkyl)-,R⁶C(═O)NR⁷(C₀-C₄ alkyl)-, R⁶OC(═O)NR⁷(C₀-C₄ alkyl)-, R⁶OC(═NCN)NR⁷(C₀-C₄alkyl)-, R⁶R⁷NC(═O)NR⁸(C₀-C₄ alkyl)-, R⁶R⁷NC(═NCN)NR⁷(C₀-C₄ alkyl)-,R⁶R⁷NC(═C(H)(NO₂))NR⁷(C₀-C₄ alkyl)-, R⁷R⁸N C(═NR⁷)NR⁷(C₀-C₄ alkyl)-,R⁶R⁷N SO₂NR⁸(C₀-C₄ alkyl)-, R⁶SO₂NR⁷(C₀-C₄ alkyl)-, R⁶S(C₀-C₄ alkyl)-,R⁶S(═O)(C₀-C₄ alkyl)-, R⁶SO₂(C₀-C₄ alkyl)-, SO₂NR⁶R⁷, SiMe₃, R⁶R⁷N(C₂-C₄alkyl)-, R⁶R⁷N(C₂-C₄ alkoxy)-, HSO₃, HONH—, R⁶ONH—, R⁸R⁷NNR⁶—,HO(COR⁶)N—, HO(R⁶O₂C)N, C₂-C₆ alkenyl, C₃-C₁₀ cycloalkyl, C₃-C₁₀cycloalkylmethyl, aryl, heteroaryl, arylO—, and aryl(C₁-C₅ alkyl)-, wherein said aryl groups are substituted with 0-2 substituentsindependently selected from a group consisting of C₁-C₄ alkyl, C₁-C₄alkoxy, F, Cl, Br, CF₃, and NO₂; (21) R¹⁵ is selected from the groupconsisting of H, C₁-C₈ alkyl, C₃-C₆ alkenyl, and C₃-C₁₀ cycloalkyl(C₀-C₄alkyl)-, aryl(C₀-C₄ alkyl)-, and heterocyclic(C₀-C₄ alkyl)-,  whereinsaid aryl or heterocyclic groups are substituted with 0-2 substituentsindependently selected from R¹⁴; and (22) R¹⁶ is selected from the groupconsisting of H, C₁-C₈ alkyl, C₃-C₆ alkenyl, C₃-C₁₀ cycloalkyl(C₀-C₄alkyl)-, aryl(C₀-C₄ alkyl)-, and heterocyclic(C₀-C₄ alkyl)-,  whereinsaid aryl or heterocyclic groups are substituted with 0-2 substituentsindependently selected from R¹⁴; (23) alternatively, when R¹⁵ and R¹⁶are on adjacent carbon atoms [as in —HR¹⁵C—CHR¹⁶—], or when R¹⁵ and R¹⁶are oriented on the same side of the double bond [as in structure (III),

 R¹⁵ and R¹⁶ can be taken together with the carbon atoms to which theyare attached to form a 3-7 membered carbocyclic aromatic or nonaromaticring system, or a 3-7 membered heterocyclic aromatic or nonaromatic ringsystem, said carbocyclic or heterocyclic ring being optionallysubstituted with 0-2 substituents independently selected from the groupconsisting of C₁-C₄ alkyl, C₁-C₄ alkoxy, F, Cl, Br, CF₃, NO₂.
 21. Apharmaceutical composition for the treatment of an IMPDH-associateddisorder, comprising a pharmaceutically acceptable carrier, adjuvant orvehicle and at least one compound of claim 20, or a pharmaceuticallyacceptable salt thereof, in an amount effective therefor.
 22. A methodfor the treatment of an IMPDH-associated disorder, comprising the stepof administering to a subject in need thereof an amount effectivetherefor of at least one compound of claim 20 or a pharmaceuticallyacceptable salt thereof.